CA2425841C - Angiostatic steroids - Google Patents

Angiostatic steroids Download PDF

Info

Publication number
CA2425841C
CA2425841C CA002425841A CA2425841A CA2425841C CA 2425841 C CA2425841 C CA 2425841C CA 002425841 A CA002425841 A CA 002425841A CA 2425841 A CA2425841 A CA 2425841A CA 2425841 C CA2425841 C CA 2425841C
Authority
CA
Canada
Prior art keywords
beta
alpha
oh
r27
ch2
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
CA002425841A
Other languages
French (fr)
Other versions
CA2425841A1 (en
Inventor
Abbot F. Clark
Raymond E. Conrow
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alcon Manufacturing Ltd
Original Assignee
Alcon Laboratories Inc
Alcon Manufacturing Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US79616991A priority Critical
Priority to US07/796,169 priority
Priority to US89244892A priority
Priority to US07/892,448 priority
Priority to US07/941,485 priority
Priority to US07/941,485 priority patent/US5371078A/en
Priority to CA 2123405 priority patent/CA2123405C/en
Application filed by Alcon Laboratories Inc, Alcon Manufacturing Ltd filed Critical Alcon Laboratories Inc
Publication of CA2425841A1 publication Critical patent/CA2425841A1/en
Application granted granted Critical
Publication of CA2425841C publication Critical patent/CA2425841C/en
Anticipated expiration legal-status Critical
Application status is Expired - Lifetime legal-status Critical

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids
    • A61K31/57Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane, progesterone
    • A61K31/573Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane, progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids
    • A61K31/565Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids
    • A61K31/565Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/569Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids
    • A61K31/57Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane, progesterone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids
    • A61K31/58Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/66Phosphorus compounds
    • A61K31/665Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J11/00Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 3
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J3/00Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J41/00Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0005Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J41/00Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0005Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
    • C07J41/0027Azides
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J5/00Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C07J5/0046Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
    • C07J5/0053Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J51/00Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J9/00Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

Abstract

Angiostatic steroids for use in controlling neovascularization and ocular hypertension are disclosed.
Pharmaceutical compositions of the angiostatic steroids and methods for their use in treating neovascularization and ocular hypertension, including controlling the ocular hypertension associated with primary open angle glaucoma, are disclosed. In addition, the combination of the compounds with glucocorticoids for the prevention of elevated intraocular pressure during the treatment of inflammation is disclosed.

Description

73498-lOD

ANGIOSTATIC STEROIDS
Backctround of the Invention The present divisional application is divided out of parent application Serial No. 2,123,405, filed November 23, 1992.
Field of the Invention The invention of the parent application relates to angiostatic steroids for controlling ocular hypertension. The compounds are also useful in preventing and treating neovascularization. Specifically, the invention is directed to new angiostatic steroids, pharmaceutical compositions comprising the angiostatic steroids, and methods of treatment which comprise administering these compositions to treat ocular hypertension, including controlling ocular hypertension associated with primary open angle glaucoma, and to treat neovascularization. In addition, the compounds can be used in combination with glucocorticoids to treat ocular inflammation without the significant intraoc:ular pressure rise commonly associated with the use of gluc:ocorticoids.
The invention of the present application relates to compounds of structures A and B as set out herein.
Description of Related Art Steroids functioning to inhibit angiogenesis in the presence of heparin or specific: heparin fragments are disclosed in Crum, et al., A New Class of Steroids Inhibits Angiogenesis in the Presence of Heparin or a Heparin Fragment, Science, Vo1.230, pp.1375-1378 (December 20, 1985). The authors refer to such steroids as "angiostatic" steroids. Included within the new class of steroids found to be angiostatic are the 73498-lOD
1a dihydro and tetrahydro metabolites of cortisol and cortexolone.
In a follow-up study directed to testing a hypothesis as to the mechanism by which the steroids inhibit angiogenesis, it was shown that heparin/angiostatic steroid compositions cause dissolution of the basement membrane scaffolding to which anchorage dependent endothelia are attached resulting in capillary involution; see, Ingber, et al., A Possible Mechanism for Inhibition of Angiogenesis by Angiostatic Steroids:
Induction of Capillary Basement Membrane Dissolution, l0 Endocrinology Vol. 119, pp.1768-1775 (1986).
A group of tetrahydro steroids useful in inhibiting angiogenesis is disclosed in International Patent Publication No. W087/02672 published May 7, 1987, Aristoff, et al., (The Upjohn Company). The compounds are disclosed for use in treating head trauma, spinal trauma, septic or traumatic shock, stroke and hemorrhage shock. In addition, the patent application discusses the utility of these compounds in embryo implantation and in the treatment of cancer, arthritis and s arteriosclerosis. Some of the steroids disclosed in Aristoff et al. are disclosed in U.S. Patent No. 4,771,042 in combination with heparin or a heparin fragment for inhibiting angiogenesis in a warm blooded animal.
Compositions of hydrocortisone, "tetrahydrocortisol-S," and U-72,7456, each in combination with a beta cyclodextrin, have been shown to inhibit io corneal neovascularization: Li, et al., Angiostatic Steroids Potentiated by Sulphated Cyclodextrin Inhibit Corneal Neovascularization, Investigative Ophthalmology and Visual Science, Vo'1. 32, No. 11, pp. 2898-2905 (October, 1991). The steroids alone reduce neovascularization somewhat but are not effective alone in effecting regression of neovascularization.
i5 Tetrahydrocortisol (THF) has been disclosed for its use in lowering the intraocular pressure (IOP) of rabbits made hypertensive with dexamethasone alone, or with dexamethasone/5-beta-dihydrocortisol; see Southren, et al., Intraocular Hypotensive Effect of a Tapically Applied Cortisol Metabolite: 3-alpha, 5-beta-tetrahydrocortisol, Investigative Ophthalmology and Visual 2o Science, Vol .28 (May, 1987) . The authors suggest THF may be useful as an antiglaucoma agent. In U.S. Patent No. 4,863,912, issued to Southren et al.
on September 5, 1989, pharmaceutical compositions containing THF and a method for using these compositions to control intraocular pressure are disclosed.
THF has been disclosed as an angiostatic steroid in Folkman, et al., 25 Angiostatic Steroids, Ann. Surg., Vo1.206, No.3 (1987) wherein it is suggested angiostatic steroids may have potential use for diseases dominated by abnormal neovascularization, including diabetic retinopathy, neovascular glaucoma and retrolental fibroplasia.
Many compounds classified as glucocorticoids, such as dexamethasone and 3o prednisolone, are very effective in the treatment of inflammed tissues;
however, when these compounds are topically applied to the eye to treat ocular inflammation, certain patients experience elevated intraocular pressure.
Patients who experience these elevations when treated with glucocorticoids are generally referred to as "steroid responders." These pressure elevations are of particular concern to patients who already suffer from elevated intraocular pressures, such as glaucoma patients. In addition, there is always a risk that the use of glucocorticoids in patients having normal intraocular pressures will cause pressure rises great enough to damage ocular tissues. Since glucocorticoid therapy is frequently long term (i.e., several days or more), there is potential for significant damage to ocular tissue as a result of prolonged elevations in intraocular pressure attributable to that therapy.
The follcw:ina articles may be referenced for further background information concerning the well-recognized association between ophthalmic glucocorticoid therapy and elevations in intrao~=ular pressure:
Kitazawa, Increased Intraocular Pressure Induced by Corticosteroids, Am. J. Ophthal., Voi.82 pp.492-493 (1976);
Cantrill, et Gl., Comparison of In Vitro Potency of Corticosteroids w.i th Ability to Raise Intraocular Pressure, Am. ~. Cphthal., Vo1.79 pp.1012-1016 (1975);
and Mindel, et a1 . , Cc~mparat:ive Ocular Pressure Elevation by Medrysone, Fluc:~rometholone, and Dexamethasone Phosphate, Arch. Ophthal.., Vo1.98 pp.1577-1578 (1980).
Commonly assigned LJ.S. Patent No. 4,945,089 discloses the use of the angiostatic steroid tetrahydrocortexolone in combination with a glucocorticoid to treat ocular inflammation without the intraccular pressure elevating effect commonly associated with topical administration of glucocorticoids. In addition, commonly assigned International Publication No.
w091/03245 published on March 21, 1991, discloses the 3a angiostatic steroids of Arist:off, et al. in combination with glucocorticoids to treat ocu7_ar inflammation without significant increase in intraocular pressure.

73498-lOD

Summary of the Invention This invention is directed to angiostatic steroids and methods of using compositions of these steroids in inhibiting neovascularization. The compositions containing the steroids can be used for treatment of angiogenesis dependent diseases, for example: head trauma, spinal trauma, septic or traumatic shock, stroke, hemorrhagic shock, cancer, arthritis, arteriosclerosis, angiofibroma, arteriovenous malformations, corneal graft neovascularization, delayed wound healing, diabetic retinopathy, granulations, burns, hemangioma, hemophilic joints, hypertrophic scars, neovascular glaucoma, nonunion fractures, Osler-Weber Syndrome, psoriasis, pyogenic granuloma, retrolental fibroplasia, pterigium, scleroderma, trachoma, vascular adhesions, and solid tumor growth. In particular, the angiostatic steroids and compositions thereof are useful for controlling ocular neovascularization.
The invention also encompasses methods for controlling ocular hypertension and glaucoma through the systemic or local administration of the compositions disclosed herein.
The present invention also includes the use of the angiostatic steroids in combination with glucocorticoids for the treatment of ocular inflammation. The addition of at least one angiostatic steroid makes i.t possible to employ the potent antiinflammatory glucocorticoids without producing significant elevations in intraocular pressure.
According to one aspect of the invention disclosed in the parent application, there is provided topical, systemic or intraocular use of a pharmaceutically effective amount of an angiostatic steroid selected from the group consisting of:
4,9(11)-Pregnadien-17a,21-diol--3,20-dione-21-acetate;

73498-lOD
4a 4,9(11)-Pregnadien-17x,21-diol-3,20-dione; 11-Epicortisol;
17x-Hydroxyprogesterone; and Tetrahydrocortexolone (THS), for preventing or treating ocular neovascularization.
According to another aspect of the invention disclosed in the parent application, there is provided a commercial package comprising a pharmaceutically effective amount of an angiostatic steroid selected from the group consisting of: 4,9(11)-Pregnad:ien-17x,21-diol-3,20-dione-21-acetate; 4,9(11)-Pregnadien-l7cx,21-diol-3,20-dione;
11-Epicortisol; 17x-Hydroxyprogesterone; and Tetrahydrocortexolone (THS), together with instructions for its use in preventing or treating ocular neovascularization.
According to still another aspect of the invention disclosed in the parent application, there is provided topical, systemic or intraocular use of a pharmaceutically effective amount of an angiostatic steroid selected from the group consisting of: 4,9(11)-Pregnadien-17x,21-diol-3,20-dione-21-acetate; 4,9(11)-Pregnadien-17x,21-diol-3,20-dione;
11-Epicortisol; 17x-Hydroxyprogesterone; and Tetrahydrocortexolone (THS), for preventing or treating ocular neovascularization of tissues in the front or the back of an eye of a host.
According to yet another aspect of the invention disclosed in the parent application, there is provided a commercial package comprising a pharmaceutically effective amount of an angiostatic steroid selected from the group consisting of: 4,9(11)-Pregnadien-17x,21-diol-3,20-dione-21-acetate; 4,9(11)-Pregnadien-17x,21-diol-3,20-dione;
11-Epicortisol; 17x-Hydroxyprogesterone; and Tetrahydrocortexolone (THS), together with instructions for its 73498-lOD
4b use in preventing or treating ocular neovascularization of tissues in the front or the back of an eye of a host.
According to a further aspect of the present invention, there is provided use of a therapeutically effective amount of a composition comprising an ophthalmically acceptable excipient and a compound of the formula:

R3 Iz t Rto t1 13 9 14 is 9 R24 to a 4 6 w R~3 R6 Rt2 Rya Rs Structure [A]
n R25 R~
R~3 Structure [B]
wherein R1 is H, ~3-CH3 or (3-C2H5; R2 is F, C9-C11 double bond, C9-C11 epoxy, H or C1; R3 is H, OR26, OC (=O) R2~, halogen, C9-C11 double bond, C9-C11 epoxy, =O, -OH, -0- alkyl (C1-C12) , -OC (=0) alkyl (C1-C12) , -OC (=0) N (R) 2 or -OC (=0) ORS, and R is hydrogen, alkyl (C1-C4), or phenyl and each R is the same or different, and R~ is alkyl (C1-C12) ; R4 is H, CH3, C1 or F; RS is H, OH, F, C1, Br, CH3, phenyl, vinyl or allyl; R6 is H or CH3;

2 5 R9 i s CH2 CH20R26 , CH2CH20C ( =O ) R2 ~ , H , OH , CH3 , F , =CHZ , CH2C (=O) ORzB, OR26, 0 (C=O) Rz-, or O (C=O) CH2 (C=O) ORz6; Rlo is -C=CH, 73498-lOD
4c -CH=CHz, halogen, CN, N3, ORz6, OC (=0) Rz-,, H, OH, CH3 or Rlo forms a second bond between positions C-16 and C-17; Rlz is H or forms a double bond with R1 or R14; R13 is halogen, ORz6, OC (=O) Rz-,, NHz, NHRzs, NHC (=O) Rz~, N (Rzs) z ~ NC (=O) Rz~, N3 ~ H, -OH, =O, P (=O) (OH) z, or -O-C (=0) - (CHz) COON where t is an integer from 2 to 6; R14 is H or forms a double bond with Rlz; Rls is H, =0 or -OH; R23 is -OH, O-C (=O) -'R11, -OP (O) - (OH) 2, -O-C (=O) - (CH2) tCOOH
or Rz3 with Rlo forms a cyclic phosphate wherein t is an integer from 2 to 6; and Rll is -Y- (CH2)n-X- (CHz)m-S03H, -Y' - (CHz)P-X' - (CHz) q-NR16R1~ or -Z (CHz) rQ, wherein, Y is a bond or -O-; Y' is a bond, -0-, or -S-; each of X and X' is a bond, -CON (R18) -, -N (Rle) CO-, -0-, -S-, -S (0) -, or -S (Oz) -; Rla is hydrogen or alkyl (C1-C4) ; each of R16 and Rl-, is a lower alkyl group of from 1 to 4 carbon atoms optionally substituted with one hydroxyl; n is an integer of from 4 to 9; m is an integer of from 1 to 5; p is an integer of from 2 to 9; q is an integer of from 1 to 5; Z is a bond or -O-; r is an integer of from 2 to 9; and Q is one of the following: (1) -R19-CH2COOH, wherein R19 is -S-, -S (0) -, -S (0) z-, -SOzN (Rzo) -, or N (Rzo) SOz-; and Rzo is hydrogen or lower alkyl-(C1-C4); with the proviso that the total number of carbon atoms is Rzo and (CHz)r is not greater than 10 ; or (2 ) -CO-COOH; or (3 ) CON (Rzl) CH (Rz2) COOH, wherein Rzl is H and Rzz is H, CH3, -CH2COOH, -CHzCHZCOOH, -CHzOH, -CH2SH, -CHzCH2SCH3, or -CH2Ph-OH, wherein Ph-OH is p-hydroxyphenyl; or Rzl is CH3 and R22 is H; or -N (Rzl) CH (Rzz) COOH is -NHCH2CONHCH2COOH; and pharmaceutically acceptable salts thereof; with the proviso that if R23 is a phosphate, it must form a cyclic phosphate, with Rlo when R13 is =O, except for the compound, wherein R1 is (3-CH3, Rz and R3 taken together form a double bond between positions 9 and 11, R4 and R6 are hydrogen, Rlz and R14 taken together form a double bond between positions 4 and 5, RS is a,-F, R9 is (3-CH3, Rlo is a-OH, R13 and Rls are =O and Rz3 is -OP (O) - (OH) z; Rz4 is C or O, and there may be a double bond between positions 1 and 2 when Rz4 is C; Rzs is 73498-lOD
4d C (R15) CHz-Rz3, OH, ORzs, OC (=0) Rz~, Rzs, COOH, C (=0) ORzs, CHOHCHzOH, CHOHCH20Rzs, CHOHCH20C (=O) Rz~, CHzCH20H, CH2N (Rzs) z, CHzOH, CHzORzs, CH20 (C=0) Rz~, CH20 (P=0) (OH) z, CHzO (P=O) (ORzs) 2, CH2SH, CH2S-Rzs, CH2SC (=O) Rz~, CH2NC (O) Rz~, C (0) CHRz80H, C (O) CHRzeORzs, C (=O) CHRzeOC (=O) Rz~ or Rlo and Rz~ taken together may be =C (Rze) z, that is, an optionally alkyl substituted methylene group;
wherein, Rzs is C1-Cs (alkyl, branched alkyl, cycloalkyl, haloalkyl, aralkyl, aryl; Rz., is Rzs or ORzs; Rz8 is H, C1-Cs (alkyl, branched alkyl, cycloalkyl); excepted from the compounds of Structure [A] are the compounds, wherein Rz3 is OH, OC (=O) R11, OP (O) (OH) z, or OC (=0) (CHz) tCOOH; also excepted from the compounds of Structure [A] are the compound 3,11~3,17a,21-tetrahydroxy-5-pregnane-20-one (the 3-a, 5-(3; 3-a, 5-a; 3-(3, 5-a; and 3-(3, 5-(3 isomers of tetrahydrocortisol) , wherein R15 is =O, Rlo is a-OH, R1 is (3-CH3, R3 is (3-OH, Rz is H, R4 is H, R13 is a- or (3-OH, R14 is H, Rlz is a- or (3-H, RS is H, Rs is H, R9 is H, Rz4 is C, and Rz3 is OH; for preventing or treating neovascularization.
According to yet a further aspect of the present invention, there is provided use of a therapeutically effective amount of a composition comprising an ophthalmically acceptable excipient and a compound of the formula:
R1 R2s 1z 1~ Rto ~ 9 14 2 5 R24 1 o R F
:3 5 Z ;.
4. 6 Structure [A]

73498-lOD
4e R~ R2s R3 R~ o I

R~ 3~
Rs Structure [B]
wherein R1 is H, (3-CH3 or (3-C2H5; R2 is F, C9-C11 double bond, C9-C11 epoxy, H or C1; R3 is H, OR26, OC (=0) R2~, halogen, C9-C11 double bond, C9-C11 epoxy, =O, -OH, -O- alkyl (C1-C12) , -OC (=O) alkyl (C1-C12) , -OC (=0) N (R) 2 or -OC (=O) ORS, and R is hydrogen, alkyl (C1-C4), or phenyl and each R is the same or different, and R~ is alkyl (C1-C=12) ; R4 is H, CH3, Cl or F; RS is H, OH, F, C1, Br, CH3, phenyl, 'vinyl or allyl; R6 is H or CH3;
R9 i s CH2CH20R26 , CH2CH20C ( =O ) R2~ , H , OH , CH3 , F , =CH2 , CHzC (=0) OR2a, OR26, O (C=0) Rz-, or 0 (C=O) CH2 (C=O) ORz6; Rlo is -C=CH, -CH=CH2, halogen, CN, N3, OR26, OC (=O) R2~, H, OH, CH3 or Rlo forms a second bond between positions C-16 and C-17; R12 is H or forms a double bond with R1 or R14; R13 is halogen, OR26, OC (=0) Rz~, NH2, NHR26, NHC (=O) R2~, N (Rzs) z, NC (=0) Rz~, N3, H, -OH, =0, -O-P (=O) (OH) 2, or -0-C (=O) - (CH2 ) tCOOH where t is an integer from 2 to 6; R14 is H or forms a double bond with R12; Rls is H, =0 or -OH; R23 is -OH, O-C (=O) -R11, -OP (0) - (OH) 2, -O-C (=O) - (CHZ) tCOOH
or R23 with Rlo forms a cyclic phosphate wherein t is an integer from 2 to 6; and R11 is -Y- (CH2)n-X- (CH2)m-S03H, -Y' - ( CH2 ) p-X' - ( CH2 ) q-NR16R1~ or -Z ( CH2 ) rQ, wherein, Y is a bond or -O-; Y' is a bond, -O-, or -S-; each of X and X' is a bond, -CON (R18) -, -N (Rle) CO-, -O-, -S-, -S (O) -, or -S (02) -; Rle is hydrogen or alkyl (C1-C4) ; each of Rls and Rl~ is a lower alkyl group of from 1 to 4 carbon atoms optionally substituted with one hydroxyl; n is an integer of from 4 to 9; m is an integer of from 1 to 5; p is an integer of from 2 to 9; q is an integer of from 1 to 5; Z is a bond or -O-; r is an integer of from 2 73498-lOD
4f to 9; and Q is one of the following: (1) -R19-CH2COOH, wherein R19 is -S-, -S (O) -, -S (O) 2-, -SO2N (R2o) -, or N (R2o) S02-; arid R2o is hydrogen or lower alkyl-(C1-C4); with the proviso that the total number of carbon atoms is R2o and (CH2)r is not greater than 10; or (2) -CO-COON; or (3) CON(R21)CH(R22)COOH, wherein R21 is H and R22 is H, CH3, -CH2COOH, -CH2CH2COOH, -CH20H, -CH2SH, -CH2CH2SCH3, or -CH2Ph-OH, wherein Ph-OH is p-hydroxyphenyl; or R21 is CH3 and R22 is H; or -N (R21) CH (R22) COOH is -NHCHzCONHCH2COOH; and pharmaceutically acceptable salts thereof; with the proviso that if R23 is a phosphate, it must form a cyclic phosphate, with Rlo when R13 is =0, except for the compound, wherein R1 is (3-CH3, R2 and R3 taken together form a double bond between positions 9 and 11, R4 and R6 are hydrogen, R12 and R14 taken together form a double bond between positions 4 and 5, RS is a-F, R, is (3-CH3, Rlo is a-OH, R13 and R15 are =O and R23 is -OP(O)-(OH)2, R24 is C or O, and there may be a double bond between positions 1 and 2 when R24 is C; R25 is C (R15) CH2-R23, OH, OR26, OC (=O) R2~,, R26, COOH, C (=O) OR26, CHOHCH20H, CHOHCH20R26, CHOHCH20C (=0) R2~, CH2CH20H, CH2CH20R26, CH2CH20C (=O) R2~, 2 0 CH2CN, CH2N3 , CH2NH2 , CH2NHR26 , CH2N ( R2s ) 2 , CH20H , CHzOR26 , CH20 (C=O) Rz~, CH20 (P=O) (OH) 2, CH2O (P=O) (0R26) 2, CH2SH, CH2S-R2s, CH2SC (=O) Rz~, CH2NC (O) R2~, C (O) CHR280H, C (O) CHR280R2s, C (=O) CHR280C (=O) Rz~ or Rlo and R25 taken together is =C (R2$) 2, that is, an optionally alkyl substituted methylene group; wherein, Rz6 is C1-C6 (alkyl, branched alkyl, cycloalkyl, haloalkyl, aralkyl, aryl; R2~ is R26 or OR2h; R28 is H, C1-C6 (alkyl, branched alkyl, cycloalkyl); excepted from the compounds of Structure A
are the compounds, wherein R23 is OH, OC (=O) R11, OP (O) (OH) 2, or OC(=O)(CH2)tCOOH; also excepted from the compounds of Structure A are the compound 3,11(3,17a,21-tetrahydroxy-5-pregnane-20-one (the 3-a, 5-~3; 3-a, 5-a; 3-(3, 5-a; and 3-(3, 5-(3 isomers of tetrahydrocortisol) , wherein R~_5 is =O, Rlo is a-OH, R1 is (3-CH3, R3 is (3-OH, R2 is H, R4 is H, R13 is a- or (3-OH, R14 is H, R12 is 73498-lOD
4g a- or ~3-H, RS is H, R6 is H, R9 is H, Rz4 is C, and R23 is OH; for preventing or treating ocular neovascularization.
According to still a further aspect of the'present invention, there is provided use of a therapeutically effective amount of a composition comprising an ophthalmically acceptable excipient and a compound selected from the group consisting of:
21-nor-5(3-pregnan-3a,17a,20-triol-3-acetate; 21-nor-5a-pregnan-3a,17a,20-triol-3-phosphate; 21.-nor-5(3-pregn-17(20)en-3a, 16-diol; 2lnor-5(3-pregnan-3a, 17(3,20-triol; 20-acetamide-21-nor-5(3-pregnan-3a,17a-diol-3-acetate; 3(3-acetamido-5(3-pregnan-113,17a,21-triol-20-one-21-acetate; 21-nor-5a-pregnan-3a,17(3,20-triol; 21a-methyl-5(3-pregnan-3a,11(3,17a,21-tetrol-20-one-21-methyl ether; 20-azido-21-nor-5(3-pregnan-3a,17a-diol;
20(carbethoxymethyl)thio-21-nor-5(3-pregnan-3a,17a-diol;
20-(4-fluorophenyl)thio-21-nor-5(3-pregnan-3a,17a-diol;
16a- (2-hydroxyethyl) -17(3-methyl.-5(3-androstan-3a, 17a-diol;
20-cyano-21-nor-5(3-pregnan-3a,1.7a-diol; 17a-methyl-5(3-androstan-3a,17~3-diol; 21-nor-5~i-pregn-17(20)en-3a-ol;
21-or-5(3-pregn-17(20) en-3a-ol-3-acetate; 21-nor-5-pregn-17(20)-en-3a-ol-16-acetic acid 3-acetate; 3~3-azido-5(3-pregnan-113, 17a, 21-triol-20-one-21-acetate; and 5(3-pregnan-113, 17a, 21-triol-20-one; 4-androsten-3--one-17(3-carboxylic acid;
17a-ethynyl-5(10)-estren-173-0l_-3-one; and 17a-ethynyl-1,3,5(10)-estratrien-3,17(3-diol, for preventing or treating ocular neovascularization.
According to another aspect of the invention disclosed in the parent application, there is provided use of a pharmaceutically effective amount of a compound selected from the group consisting of: 21-met:hyl-5~3-pregnan-3a,11~,17a,21-tetrol-20-one-21-methyl ether; 3~-azido-5~i-pregnan-11(3,17a,21-73498-lOD
4h triol-20-one-21-acetate; 3~-acetamido-5~-pregnan-11~,17a,21-triol-20-one-21-acetate; 20-(4-fluorophenyl)thio-21-nor-5a-pregnan-3a,17a-diol; 20-azido-21-nor-5~-pregnan-3a,17a-diol;
20-(carbethoxymethyl)thin-21-nor-5a-pregnan-3a,17a-diol;
20-acetamido-21-nor-5~-pregnan-3a,17a-diol-3-acetate;
16a-(2-hydroxyethyl)-17R-methyl-5~-androstan-3a,17a-diol;
20-cyano-21-nor-5a-pregnan-3a,17a-diol; 17a-methyl-5a-androstan-3a,17~-diol; 21-nor-5~-pregnan-17(20)-en-3a-ol;
21-nor-5~-pregnan-17(20)-en-3a-ol-3-acetate; 21-nor-5~-pregnan-17(20)-en-3a-ol-16-acetic. acid-3-acetate; 21-nor-5R-pregnan-3a,17a,20-triol; 21-nor-5~-pregnan-3a,17a,20-triol-3-acetate;
21-nor-5a-pregnan-17(20)-en-3a,16-diol-3-acetate-16-(O-methyl) malonate; 21-nor-5a-pregnan-3a,17a,20-triol-3-phosphate;
21-nor-5~-pregnan-17(20)-en-3a,16-diol; 21-nor-5~-pregnan-3a,17~,20-triol; 21-nor-5a-pregnan-~a,17~,20-triol;
4-androsten-3-one-173-carboxylic acid; 17a-ethynyl-5(10)-estren-17~-0l-3-one; 17a-ethynyl-1,3,5(10)-estratrien-3,17a-diol; and 4,9(11)-pregnadien-17a,21-diol-3,20-dione-21-acetate, for controlling ocular hypertension.
According to yet another aspect of the invention disclosed in the parent application, there is provided a composition for controlling ocular hypertension comprising an ophthalmically acceptable excipient and a pharmaceutically effective amount of a compound selected from the group consisting of: 21-methyl-5~-pre>.gnan-3a,11~,17a,21-tetrol-20-one-21-methyl ether; 3R-azido-_'~R-pregnan-11~,17a,21-triol-20-one-21-acetate; 3~-acetarnido-5~~-pregnan-11~,17a,21-triol-20-one-21-acetate; 20-(4-fluorophE;nyl)thio-21-nor-5~-pregnan-3a,17a-diol; 20-azido-21-nor-5~~-pregnan-3a,17a-diol;
20-(carbethoxymethyljthio-21-nor-5~-pregnan-3a,17a-diol;
20-acetamido-21-nor-5~-pregnan-3a,17a-diol-3-acetate;
16a-(2-hydroxyethyl)-17~-methyl-5~-androstan-3a,17a-diol;
20-cyano-21-nor-5~-pregnan-3a,7_7a-diol; 17a-methyl-5~-73498-lOD
4i androstan-3a,17~-diol; 21-nor-5~i-pregnan-17(20)-en-3a-ol;
21-nor-5~i-pregnan-17(20)-en-3a-ol-3-acetate; 21-nor-5~i-pregnan-17(20)-en-3a-ol-16-acetic acid-3-acetate; 21-nor-5a-pregnan-3a,17a,20-triol; 21-nor-5a-pregnan-3a,17a,20-triol-3-acetate;
21-nor-5(3-pregnan-17(20)-en-3a,16-diol-3-acetate-16-(0-methyl) malonate; 21-nor-5a-pregnan-3a,17a,20-triol-3-phosphate;
21-nor-5(3-pregnan-17(20)-en-3x,16-diol; 21-nor-5(3-pregnan-3a,17~i,20-triol; 21-nor-5a-pregnan-3a,17~,20-triol;
4-androsten-3-one-17(3-carboxylic acid; 17a-ethynyl-5(10)-estren-173-0l-3-one; 17a-ethynyl-1,3,5(10)-estratrien-3,17(3-diol; and 4,9(11)-pregnadien-17a,21-diol-3,20-dione-21-acetate.
According to another aspect of the invention disclosed in the parent application, there is provided a pharmaceutical composition useful in the treatment of ophthalmic inflammation, comprising: an ophthalmically acceptable excipient, an antiinflammatory effective amount of a glucocorticoid and an intraocul.ar pressure controlling amount of an angiostatic steroid selected from the group consisting of: 21-Nor-5(3-pregnan-3a,17a,20-triol-3-acetate; 21-Nor-5a-pregnan-3a,17a,20-triol-3-phosphate; 21-Nor-5(3-pregn-17(20)en-3a,16-diol; 21-Nor-5(3-pregnan-3a,17(3,20-triol; 20-Acetamide-21-nor-5~3-pregnan-3a,17a-diol-3-acetate; 3(3-Acetamido-5(3-pregnan-11(3,17a,21-triol-20-one-21-acetate; 21-Nor-5a-pregnan-3a,17(3,20-triol; 21a-Methyl-5~3-pregnan-3a,11~3,17a,21-tetrol-20-one-21-methyl ether; 20-Azido-21-nor-5~3-pregnan-3a,17a-diol;
20(Carbethoxymethyl)thio-21-nor-5[3-pregnan-3a,17a-diol;
20-(4-Fluorophenyl)thio-21-nor-5(3-pregnan-3a,17a-diol;
16a-(2-Hydroxyethyl)-17(3-methyl-5[3-androstan-3a,17a-diol;
20-Cyano-21-nor-5(3-pregnan-3a,17a-diol; 17a-Methyl-5(3-androstan-3a, 17(3-diol; 21-Nor-5(3-pregn-17 (20) en-3a-oL;
21-Nor-5(3-pregn-17 (20) en-3a-ol--3-acetate; 21-Nor-5(3-pregn-73498-lOD

17(20)-3en-3a-ol-16-acetic acid 3-acetate; 3~-Azido-5~-pregnan-l1a,17a,21-triol-20-one-21-acetate; 4,9(11)-Pregnadien-17a, 21-diol-3,20-dione; 4,9(11)-Pregnadien-17a,21-diol-3,20-dione-21-acetate; 4-Androsten-3-one-17~-carboxylic acid; 17a-Ethynyl-5(10)-estren-17a-ol-3-one; 17a-Ethynyl-1,3,5(10)-estratrien-3,17-diol; and 17a-Hydroxyprogesterone.
Brief Description of the Drawing Figure 1 compares the ability of angiostatic steroids to inhibit neovascularization in the rabbit cornea.
Detailed Description of Preferred Embodiments The development of blood vessels for the purpose of sustaining viable tissue is known as angiogenesis or neovascularization. Agents which inhibit neovascularization are known by a variety of terms such as angiostatic, angiolytic or angiotropic agents. For purposes of this specification, the term "angiostatic agent" means compounds which can be used to control, prevent, or inhibit angiogenesis.
The angiostatic agents of the present invention are steroids or steroid metabolites. For purposes herein, the term "angiostatic steroids" means s steroids and steroid metabolites which inhibit angiogenesis.
There is currently no effective method for controlling the neovascularization in angiogenesis-dependent diseases. In particular, ocular neovascularization has not been successfully treated in the past.
Neovascularization of tissues in the front of the eye (i.e. the cornea, iris, is and the trabecular meshwork) and other conditions, including conditions in the back of the eye, for example, retinal, subretinal, macular, and optical nerve head neovascularization, can be prevented and treated by administration of the steroids of this invention. The angiostatic steroids of the present invention are useful in preventing and treating neovascularization, including providing is for the regression of neovascularization.
The angiostatic steroids can also be used for the control of ocular hypertension. In particular, the agents can be used for the treatment of primary open angle glaucoma.
The angiostatic steroids of the present invention have the following 2o formula:
~3 ~~ R R R~ R2s RIO
R4~ _ , R~ ~ ~ ~~6 ~3 Structure [A] Structure[B]

wherein R1 is H, ~-CH3 or ~-C2H5;
RZ is F, C9-C11 double bond, C9-C11 epoxy, H or C1;
R3 is H, OR26, OC(=0)Rz~, halogen, Cs-C11 double bond, C9-C11 epoxy, =0, -OH, -alkyl(C1-C12), -OC(=0)alkyl(C1-Clz), -OC(=0)ARYL, -OC(=0)N(R)z or s -OC(=0)OR~, wherein ARYL is furyl, thienyl, pyrrolyl, or pyridyl and each of said moieties is optionally substituted with one or two (C1-C4)alkyl groups, or ARYL is -(CHZ)f-phenyl wherein f is 0 to 2 and the phenyl ring is optionally substituted with 1 to 3 groups selected from chlorine, fluorine, bromine, alkyl(C1-C3), alkoxy(Ci-C3), thioalkoxy-(C1-C3), C13C-, F3C-, -NHz and io -NHCOCH3 and R i s hydrogen, al kyl (C1-C4) , or phenyl and each R can be the same or different, and R~ is ARYL as herein defined, or alkyl(C1-C12);
R4 i s H, CH3, C1 or F;
R5 is H, OH, F, C1, Br, CH3, phenyl, vinyl or allyl;
Rs is H or CH3;
i5 R9 is CHZCHzOR26, CHZCHZOC(=0)R2~, H, OH, CH3, F, =CHZ, CH2C{=0)ORzB,, OR26, 0(C=OjRz~ or 0(C=0)CHZ(C=0)ORZs Rlo is -C~CH, -CH=CH2, halogen, CN, N3, OR26, OC(=0)R2~, H, OH, CH3 or Rlo forms a second bond between positions C-16 and C-17;
R12 is H or forms a double bond with R1 or Rla~
Zo R13 is halogen, OR26, OC(=0)R2~, NHz, NHR26, NHC(=0)R2~, N(RZS)2~
NC(=0)R2~, N3, H, -OH, =0, -0-P(=0)(OH)2, or -0-C(=0)-(CH2)tC00H where t is an integer from 2 to 6;
R14 is H or forms a double bond with Rlz;
R15 i s H, =0 or -OH;
is and R23 with Rla forms a cyclic phosphate;
wherein Rg and R15 have the meaning defined above;
or wherein R23 is -OH, 0-C(=0)-R11, -OP(0)-(OH)Z, or -0-C{=0)-(CHZ)iC00H
wherein t is an integer from 2 to 6; and R11 is -Y-(CHZ)~-X-(CHZ)m-S03H, -Y'-(CH2)p-X'-(CHz)q-NR16R1~ or -Z(CHZ)~Q, 3o wherein Y is a bond or -0-; Y' is a bond, -0-, or -S-; each of X and X' is a bond,-CON(R18)-, -N(R18)CO-, -0-, -S-~, -S(0)-, or -S(OZ)-; R18 is hydrogen or alkyl (C1-C4); each of R16 and R1~ is a lower alkyl group of from 1 to 4 carbon atoms optionally substituted with one hydroxyl or R16 and R1~ taken together with the nitrogen atom to. which each is attached forms a monocyclic 3s heterocycle selected from pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino or N(lower)alkyl-piperazino wherein alkyl has from 1 to 4 carbon atoms; n is an integer of from 4 to 9; m is an integer of from 1 to 5; p is an integer of from 2 to 9; q is an integer of from 1 to 5;
Z i s a bond or -0- ; r i s an i nteger of from 2 to 9; and Q i s one of the following:
(1) -R19-CHZCOOH wherein R19 is =S-, -S(0)-, -S(0)z-, -SOzN(Rzo)-, or s N(R2o)SOZ-; and RZO is hydrogen or lower alkyl-(C1-C4); with the proviso that the total number of carbon atoms in RZO and (CHZ)~ is not greater than 10; or (Z) -CO-COOH; or (3) CON(R21)CH(R22)COOH wherein Rzl is H and R22 is H, CH3, -CHZCOOH, -CH2CHzC00H, -CH20H, -CHzSH, -CHZCH2SCH3, or io -CHZPh-OH wherein Ph-OH is p-hydroxyphenyl;
or R21 i s CH3 and R2Z i s H;
or R21 and Rzz taken together are -CHZCHzCH2-;
or -N(R21)CH{RzZ)COOH taken together is -NHCHZCONHCHZCOOH; and pharmaceutically acceptable salts thereof;
i5 with the proviso that except for the compound wherein R1 is ~-CH3, RZ and taken together form a double bond between positions 9 and 11, R4 and R6 are hydrogen, R12 and R14 taken together form a double bond between positions 4 and 5, R5 is «-F, R9 is ~-CH3, Rio is «-OH, R13 and R1J are =0 and Rz3 is -OP(0) (OH)2, R13 is =0 only when R23 with Rlo forms the above described cyclic 2o phosphate.
Rz4 = C, C1-C2 double bond, 0;
R25 = C(R15)CHZ-R23, OH, ORZ6, OC(=0)R2>> RZS, COOH, C(=0)OR26, CHOHCH20H, CHOHCHZORZ6, CHOHCHZOC(=0)R2~, CHzCHZOH, CHZCH20R26, CHZCHZOC(=0)RZ~, CHZCN, CHZN3, CHzNH2, is CHzNHRZS, CHZN(RZ6)2, CHZOH, CHZORZ6, CH20(C=0)RZ~, CHZO{P=0) (0H)2, CH20(Pi0) (ORZ6)~ , CH~SH, CH2S-R26, CHZSC(=0)R~~, CH2NC (=0 ) R2~, C (=0 ) CHRZSOH, C ( =0 ) CHRZ80R26, C (=0 ) CHRzeOC (=0 ) RZ~ or Rlo and R25 taken together may be =C(R28)2, that is, an optionally alkyl substituted methylene group;
3o wherein R26 = C1-Cs (alkyl, branched alkyl, cycloalkyl, haloalkyl, aralkyl, aryl); R2~ = RZ6 + OR26; Rz8 = H, C1-Cfi (alkyl, branched alkyl, cycloalkyl).
Excepted from the compounds of Structure [A] are the compounds wherein R1 is ~-CH3 or ~-CZHS;
RZ is H or Cl;
35 R3 is H, =0, -OH, -0-alkyl(C1-C12), -OC(=0)alkyl(C1-C12), -OC(=0)ARYL, -OC(=0)N(R)2 or «-OC(=0)OR~, wherein ARYL is furyl, thienyl, pyrrolyl, or pyridyl and each of said moieties is optionally substituted with one or two (C1-C4)alkyl groups, or ARYL is -(CH2)f-phenyl wherein f is 0 to 2 and the phenyl ring is optionally substituted with 1 to 3 groups selected from chlorine, fluorine, bromine, alkyl(C1-C3), alkoxy(C1-C3), thioalkoxy-(C1-C3), C13C-, F3C-, -NHZ and -NHCOCH3 and R is hydrogen, alkyl (Ci-C4), or phenyl and each R can be the same or different, and R~ is ARYL as herein defined, or al kyl (C1-C1z) ;
or wherein RZ and R3 taken together are oxygen (-0-) bridging positions C-9 and io C-11; or wherein R2 and R3 taken together form a double bond between positions C-9 and C-11;
or RZ is a-F and R3 is ~-OH;
or RZ is a-C1 and R3 is ~-C1;
is and R4 is H, CH3, C1 or F;
R5 is H, OH, F, C1, Br, CH3, phenyl, vinyl or allyl;
Rs i s H or CH3;
R9 is H, OH, CH3, F or =CN2;
Rlo is H, OH, CH3 or Rlo forms a second bond between positions C-16 and C-17;
2o R12 is -H or forms a double bond with Rla~
R13 is H, -OH, =0, -0-P(0)(OH)Z, or -0-C(=0)-(CHZ)LCOOH where t is an integer from 2 to 6;
R14 is H or forms a double bond with R12;
R15 i s =0 or -OH;
zs and R23 with Rlo forms a cycl is phosphate;
wherein R9 and R15 have the meaning defined above;
or wherein R23 is -OH, 0-C(=0)-R11, -OP(0)-(OH)2, or -0-C(=0)-(CH2)tC00H
wherein t is an integer from 2 to 6; and R11 is -Y-(CH2)~-X-(CHZ)m-S03H, -Y'-(CH2)p-X'-(CH2)q-NR16R1~ or -Z(CH2)1.Q, wherein Y is a bond or -0-; Y' is a 3o bond, -0-, or -S-; each of X and X' is a bond,-CON(Rl8)-, -N(Ri8)CO-, -0-, -S
-S(0)-, or -S(OZ)-; R18 is hydrogen or alkyl (C1-C4); each of R16 and R1~ is a lower alkyl group of from 1 to 4 carbon atoms optionally substituted with one hydroxyl or RI6 and Rz~ taken together with the nitrogen atom to which each is attached forms a monocyclic heterocycle selected from pyrrolidino, 35 piperidino, morphoiino, thiomorpholino, piperazino or N(lower)alkyl-piperazino wherein alkyl has from 1 to 4 carbon atoms; n is an integer of from 4 to 9;
m i s an i nteger of from 1 to 5; p i s an i nteger of from 2 to 9; q i s an integer of from 1 to 5;
Z i s a bond or -0- ; r i s an i nteger of from 2 to 9; and Q i s one of the following:
(1) -R19-CHZCOOH wherein R19 is -S-, -S(0)-, -S(0)2-, -SOZN(Rzo)-, or N(RZO)SOZ-; and RZO is hydrogen or lower alkyl-(C1-C4); with the proviso that the total number of carbon atoms in RZO and (CHZ)~ is not greater than 10; or (2) -CO-COOH; or (3) CON(R21)CH(Rz2)COOH wherein R2~ is H and R22 is H, CH3, -CH2COOH, -CHZCHZCOOH, -CHzOH, -CHZSH, -CHZCHZSCH3, or io -CH2Ph-OH wherein Ph-OH is p-hydroxyphenyl;
or R21 i s CH3 and RZZ i s H;
or RZ1 and R22 taken together are -CHZCHZCH2-;
or -N(R21)CH(RZZ)COOH taken together is -NHCHzCONHCHZC00H; and pharmaceutically acceptable salts thereof;
is with the proviso that except for the compound wherein R1 is ~-CH3, RZ and taken together form a double bond between positions 9 and 11, R4 and R6 are hydrogen, R12 and R14 taken together form a double bond between positions 4 and S, R5 i s «-F, R9 i s B-CH3, Rlo i s «-OH, R~3 and R15 are =0 and R23 i s -OP(0) =
(0H)2, Ri3 is =0 only when R23 with Rlo forms the above described cyclic 2o phosphate.
Unless specified otherwise, all substituent groups attached to the cyclopentanophenanthrene moiety of Structures [A] and [B] may be in either the alpha or beta position. Additionally, the above structures include all pharmaceutically acceptable salts of the angiostatic steroids.

Preferred angiostatic steroids for the treatment of ocular hypertension, neovascular diseases and ocular inflartmation are:
o-' > >
OH ~~OH
Ho''~
H H
21-METHYL-5~-PREGNAN-3«,11,17«, 3p-AZIDO-5~-PREGNAN-21-TETROL-20-ONE 21-METHYL ETHER 11~,17«,21-TRIOL-20-ONE-21-ACETATE
O
O
)H
'iOH

H
s 3~-ACETAMIDO-5S- 5~-PREGNAN-11,17«,21-TRIOL-ZO-ONE
PREGNAN-11~,17a, 21-TRIOL-HO '~~
S ~ ~ F
"'~ OH
H
20-(4-FLUOROPHENYL)THIO-21-NOR-5~-PREGNAN-3«,17«-DIOL

~O
N=N~=N
O
i0 H
iOH
HO "~
H HO""
H
20-AZIDO-21-NOR-5p-PREGNAN-3«, 20-(CARBETHOXYMETHYL)THIO-21-NOR-5~-17«-DIOL PREGNAN-3«,17«-DIOL
O
OH
HO ~~~
H
O
H
20-ACETAMIDO-21-NOR-5~-PREGNAN-3«, 16 -(2-HYDROXYETHYL)-17p-METHYL-17«-DIOL-3-ACETATE 5~-ANDROSTAN-3«,17«-DIOL
~N
~H
HO ~\
H
s 20-CYANO-21-NOR-5p-PREGNAN-3«,17«-DIOL

OH
HO ~~ HO ~~' H H
17«-METHYL-5~9-ANDROSTAN- 21-NOR-5~-PREGN-17(20)-EN-3«-OL
3«,17~-DIOL
o~
o, H H
21-NOR-5~-PREGN-17(20)-EN- 21-NOR-5~-PREGN-17(20)-EN-3«-OL-3«-OL-3-ACETATE 16-ACETIC ACID-3-ACETATE
H
OH
H
HO ~~' H O
H
21-NOR-5~-PREGNAN-3«,17«,20-TRIOL 21-NOR-5,B-PREGNAN-17«,20-DIOL-O
O
~H

H
~H
O
O

4,9(ll)-PREGNADIEN-17«,21-DIOL-3,20- 4,9(11)-PREGNADIEN-17«,21-DIONE-21-ACETATE DIOL-3,20-DIONE
H
O O
~H O H
O
11-EPICORTISOL 17«-HYDROXYPROGESTERONE
011 nH
O O
iH H
HO' HO~ H
H
TETRAHYDROCORTEXOLONE (THS) TETRAHYDROCORTISOL (THF) OH
OOH
,~n O O
O i O O O
~ II , ~Ov HO,P-O ~, _ H I H
OH
21-NOR-5~-PREGN-17(20)-EN-3«, 21-NOR-5«-PREGNAN-3«,17«,20-TRIOL-16-DIOL-3-ACETATE-16-(0-METHYL)MALONATE 3-PHOSPHATE
~~~~OH
HO HO ~~' off ,, OH
H H
21-NOR-5~-PREGN-17(20)-EN-3x,16-DIOL 21-NOR-5~-PREGNAN-3a,17~,20-TRIOL
OH
OH
"\OH
HO ~~, _ H O
21-NOR-5a-PREGNAN-3a,17~,20-TRIOL 4-ANDROSTEN-3-ONE-17~-CARBOXYLIC
s ACID
~H
..-s O
HO
17a-ETHYNYL-5(10)-ESTREN-17p-Ol-3-ONE 17a-ETHYNYL-1,3,5(10)-ESTRATRIEN-3,17-DIOI

Most preferred compounds for preventing and treating neovascularization are:
4,9(11)-Pregnadien-17«,21-diol-3,20-dione-21-acetate 21-Nor-5~-pregn-17(20)-en-3«,16-diol-3-acetate-16-(0-methyl)malonate 4,9(11)-Pregnadien-17«,21-diol-3,20-dione 21-Nor-5~-pregnan-3«,17«,20-triol-3-acetate 21-Nor-5«-pregnan-3«,17«,20-triol-3-phosphate The angiostatic steroids of the present invention are useful in io inhibiting neovascularization and can be used in treating the neovascularization associated with: head trauma, spinal trauma, systemic or traumatic shock, stroke, hemorrhagic shock, cancer, arthritis, arteriosclerosis, angiofibroma, arteriovenous malformations, corneal graft neovascularizatian, delayed wound healing, diabetic retinopathy, granulations, i5 burns, hemangioma, hemophilic joints, hypertrophic scars, neovascular glaucoma, nonunion fractures, Osler-Weber Syndrome, psoriasis, pyogenic granuloma, retrolental fibroplasia, pterigium, scleroderma, trachoma, vascular adhesions, and solid tumor growth.
In particular, the angiostatic steroids are useful in preventing and 2o treating any ocular neavascularization, including, but not limited to:
retinal diseases (diabetic retinopathy, chronic glaucoma, retinal detachment, sickle cell retinopathy, senile macular degeneration due to subretinal neovascularization); rubeosis iritis; inflammatory diseases; chronic uveitis;
neoplasms (retinoblastoma, pseudoglioma); Fuchs' heterochromic iridocyclitis;
is neovascular glaucoma; corneal neovascularization (inflammatory, transplantation, developmental hypoplasia of the iris); neovascularization resulting following a combined vitrectomy and lensectomy; vascular diseases (retinal ischemia, choroidal vascular insufficiency, choroidal thrombosis, carotid artery ischemia); pterigium; neovascularization of the optic nerve;
3o and neovascularization due to penetration of the eye or contusive ocular injury.

The initiation of new blood vessel formation may arise quite differently in various tissues or as a result of different diseases. Many substances have been found to induce neovascularization, see, Folkman, et al., Angiogenic Factors, Science, Volume 235, pp. 442-447 (1987). However, it is believed, s that once initiated, the process of neovascularization is similar in all tissues regardless of the associated disease, Furcht, Critical Factors Controlling Angiogenesis: Cell Products, Cell Matrix, and Growth Factors, Laboratory Investigation, Volume 55, No. 5, pp. 505-509 (1986).
There are a variety of theories regarding the mechanism of action of io angiostatic steroids. For example, angiostatic steroid induced inhibition of neovascularization may occur due to, dissolution of the capillary basement membrane, Ingber, et al., Supra; inhibition of vascular endothelial cell proliferation, Cariou, et al., Inhibition of Human Endothelial Cell Proliferation by Heparin and Steroids, Cell Biology International Reports, i5 Vol. 12, No. 12, pp. 1037-1047 (December, 1988); effect on vascular endothel i al cel l l ami ni n express i on, Toki da, et al . , Product i on of Two Vari ant Laminin Forms by Endothelial Ce)Is and Shift of Their Relative Levels by Angiostatic Steroids, The Journal of Biological Chemistry, Vol. 264, No. 30, pp. 18123-18129 (October 25, 1990); inhibition of vascular cell collagen Zo synthesis, Maragoudakis, et al., Antiangiogenic Action of Heparin Plus Cortisone is Associated with Decreased Collagenous Protein Synthesis in the Chick Chorioa)lantoic Membrane System, The Journal of Pharmacology and Experimental Therapeutics, Vol. 251, No. 2, pp. 679-682 (1989); and inhibition of vascular endothelial cell plasminogen activator activity, Ashino-Fuse, et is al., Medroxypregesterone Acetate, An Anti-Cancer and Anti-Angiogenic Steroid, Inhibits the Plasminogen Activator in Bovine Endothelial Cells, Int. J.
Cancer, 44, pp. 859-864 (1989).
There are many theories associated with the cause of neovascularization, and there may be different inducers depending on the disease or surgery 3o involved, BenEzra, Neovasculogenic Ability of Prostag)andins, Growth Factors, and Synthetic Chemoattractants, American Journal of Ophthalmology, Volume 86, No. 4; pp. 455-461, (October, 1978). Regardless of the cause or the associated disease or surgery, it is believed that angiostatic agents work by inhibiting one or more steps in the process of neovascularization. Therefore, 35 the angiostatic steroids of this invention are useful in the treatment and prevention of neovascularization associated with a variety of diseases and surgical complications.
The angiostatic steroid's of the present invention may be incorporated, together with an ophthalmically acceptable excipient, in various formulations for delivery. The type of formulation (topical or systemic) will depend on the site of disease and its severity. For administration to the eye, topical formulations can be u:~ed and can include cphthalmoiogically acceptable preservatives, surfactants, viscosity enhancers, buffers, sodium chloride, and water to form aqueous sterile op:nthalmic solutions and suspensions. In order r_o prepare sterile ophthalmic ointment formulations, an angiostatic steroid is combined with a preservative in an appropriate vehicle, such as mineral oil, liquid lanolin, or 1S white petrolatum. Sterile ophthalmic gel formulations comprising the angiostatic steroids of the present invention can be prepared by suspending an angiostatic steroid in a hydrophilic base prepared from a combination of, for example, Carbopcl~ (a carboxy vinyl polymer available from the BF
Goodrich Company) according to published formulations for analogous ophthalmic preparations. Preservatives and antimicrobial agents may also be incorporated in such gel formulations. Systemic formulations for treating ocular neovascularization can also be used, for example, orally ingested tablets and formulations for intraocular and periocular injection.
The specific type of formulation selected will depend on various factors, such as the angiostatic steroid or its salt being used, the dosage frequency, and the location of the neovascularization being treated. Topical ophthalmic aqueous solutions, suspensions, ointments, and gels are the preferred dosage forms for the treatment of neovascularization in the front of the eye (the cornea, iris, trabecular meshwork); or 17a neova scularization of the back of the eye if the angiostatic agent can be formulated such that it can be delivered topically and t he agent is able t-:~ penetrate the tissues in the front of the eye. The angiostatic steroid will normally be contained in these formulations in an amount from about 0.01 to about 10.0 weight/percent. Preferable concentrations range from about 0.1 to about 5.0 weight/percent. Thus, for topical administration, these formulations are delivered to the surface of the eye one to six times a day, depending on the routine discretion of the skilled clinician. Systemic administration, for example, in the form of tablets is useful for the treatment of neovascularization particularly of IP
the back of the eye, for example, the retina. Tablets containing 10-1000 mg of angiostatic agent can be taken 2-3 times per day depending on the discretion of the skilled clinician.
The preferred compounds for controlling ocular hypertension are: 21-Nor-5~-pregnan-3«,17«,20-triol;5~-pregnan-l1s,17«,21-triol-20-one;4,9(11)-Pregnadien-17«,21-diol-3,20-dione-21-acetate, and 4,9(11)-Pregnadien-17«,21-diol-3,20-dione. The most preferred compound is 4,9(11)-Pregnadien-17«,21-diol-3,20-dione-21-acetate.
Without intending to be bound by any theory, it is believed that the io angiostatic steroids of the type described above act to control intraocular pressure by inhibiting the accumulation or stimulating the dissolution of amorphous extracellular material in the trabecular meshwork of the eye. The presence of this amorphous extracellular material alters the integrity of the healthy trabecular meshwork and is a symptom associated with primary open is angle glaucoma (POAG). It is not well understood why this amorphous extracellular material builds up in the trabecular meshwork of persons suffering from POAG. However, it has been found that the amorphous extracellular material is generally composed of glycosaminoglycans (GAGs) and basement membrane material; see, Ophthalmology, Vo1.90, No.7 (July 1983); Mayo zo C1 in. Proc, Vol .61, pp.59-67 (Jan.1986} ; and Pediat. Neurosci . Vol .12, pp.240-251 (1985-86). When these materials build up in the trabecular meshwork, the aqueous humor, normally present in the anterior chamber of the eye, cannot leave this chamber through its normal route (the trabecular meshwork) at its normal rate. Therefore, a normal volume of aqueous humor is produced by the is ciliary processes of the eye and introduced into the anterior chamber, but its exit through the trabecular meshwork is abnormally slow. This results in a buildup of pressure in the eye, ocular hypertension, which can translate into pressure on the optic nerve. The ocular hypertension so generated can lead to blindness due to damage to the optic nerve.
3o Many methods for treating primary open angle glaucoma and ocular hypertension concentrate on blocking production of aqueous humor by the eye.
However, aqueous humor is the fundamental source of nourishment for the tissues of the eye, particularly the cornea and lens which are not sustained by blood supply. Therefore, it is not desirable to deprive these tissues of the necessary irrigation and nutrition provided by the aqueous humor. It is desirable to strive for normal exit of the aqueous humor by maintaining the normal integrity of the trabecular meshwork. This is accomplished according to the present invention by the administration of angiostatic steroids.
s It is believed that the angiostatic steroids disclosed herein function in the trabecular meshwork in a similar manner as shown by Ingber, et al., wherein it was shown that angiostatic steroids caused dissolution of the basement membrane scaffolding using a chick embryo neovascularization model;
Endocrino)ogy, 119, pp.1768-1775 (1986). It is believed that the angiostatic io steroids of the present invention prevent the accumulation, or promote the dissolution of, amorphous extracellular materials in the trabecular meshwork by inhibiting the formation of basement membrane materials and glycosaminoglycans. Thus, by preventing the development of these materials or promoting their dissolution, the normal integrity of the trabecular meshwork is i s retai ned and aqueous humor may fl ow through the trabecul ar meshwork at normal rates. As a result, the intraocular pressure of the eye is controlled.
The angiostatic steroids of the present invention may be incorporated in various formulations for delivery to the eye to control ocular hypertension. For example, topical formulations can be used and can include 20 ophthalmologically acceptable preservatives, surfactants,viscosity enhancers, buffers, sodium chloride and water to form aqueous sterile ophthalmic solutions and suspensions. In order to prepare sterile ophthalmic ointment formulations, an angiostatic steroid is combined with a preservative in an appropriate vehicle, such as mineral oil, liquid lanolin or white petrolatum.
zs Sterile ophthalmic gel formulations comprising the angiostatic steroids of the present invention can be prepared by suspending an angiostatic steroid in a hydrophilic base prepared from a combination of, for example, Carbopol~ 940 (a carboxyvinyl polymer available from the B.F. Goodrich Company) according to published formulations for analogous ophthalmic preparations.
3o Preservatives and tonicity agents may also be incorporated in such gel formulations. The specific type of formulations selected will depend on various factors, such as the angiostatic steroid or its salt being used, and the dosage frequency. Topical ophthalmic aqueous solutions, suspensions, ointments and gels are the preferred dosage forms. The angiostatic steroid 35 Will normally be contained in these formulations in an amount of from about 0.005 to about 5.0 weight percent (wt.fo). Preferable concentrations range from about 0.05 to about 2.0 wt.%. Thus, for topical administration, these formulations are delivered to the surface of the eye one to four times per day, depending upon the routine discretion of the skilled clinician.
s In addition, antiinflammatory compositions of glucocorticoids can contain one or more angiostatic steroids of the present invention, preferably tetrahydrocortisol. These compositions will contain one or more glucocorticoids in an antiinflammatory effective amount and will contain one or more angiostatic steroids of the present invention in an amount effective io to inhibit the IOP elevating effect of the glucocorticoids. The amount of each component will depend on various factors, such as the relative tendency of certain glucocorticoids to cause IOP elevations, the severity and type of ocular inflammation being treated, the estimated duration of the treatment, and so on. In general, the ratio of the amount of glucocorticoid to the is amount of angiostatic steroid on a weight to weight basis will be in the range of 10:1 to 1:20. The concentration of the glucocorticoid component will typically be in the range of about 0.01f° to about 2.0fe by weight. The concentration of the angiostatic steroid component will typically be in the range of about 0.05% to about 5.0% by weight.
2o The above-described active ingredients may be incorporated into various types of systemic and ophthalmic formulations. For example, for topical ocular administration, the active ingredients may be combined with ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, buffers, toxicity agents and water to form an aqueous, sterile ophthalmic is suspension. In order to prepare sterile ophthalmic ointment formulations, the acti ve i ngredients are combi ned wi th a preservati ve i n an appropri ate vehi c1 e, such as mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulations may be prepared by suspending the active ingredient in a hydrophilic base prepared from the combination of Carbopol~ 940 (a carboxy 3o vinyl polymer available from the B.F. Goodrich Company) according to published formulations for analogous ophthalmic preparations; preservatives and tonicity agents can also be incorporated. The specific type of formulation selected will depend on various factors, such as the severity and type of ophthalmic inflammation being treated, and dosage frequency. Ophthalmic solutions, 35 suspensions, ointments and gels are the preferred dosage forms, and topical application to the inflamed ocular tissue is the preferred route of administration.
It is evident to be skilled in the art that the compounds and compcsitions of this invention are generally sold in the form of commercial packages comprising the compound or composition together with instructions for using them in treating or preventing she var_ious conditions or diseases disclosed herein.
The following examples illustrate formulations and synthesis of compounds cf the present invention, but are in no way limiting.
Example The topical compositions are useful for controlling ocular hypertension cr controlling ocular neovascularization.
Component. wt.%
Angiostat,~c Steroid 0.005-5.0 Tyloxapol 0.01-0.05 HPMC 0.5 Benzalkonium Chloride 0.01 Sodium Chloride 0.8 Edetate Disodium 0.01 NaOH/HC1 q.s. pH 7.4 Purified Water q.s. 100 mL

21a Example 2 The composition is useful for controlling ocular hypertension.
Component:: wt . °s 21-Nor-5~3-pregnan-3c~, 17a., 20-triol 1 . 0 Tyloxapol 0.01-0.05 HPMC 0.5 Banzalkonium ~.'~hloride 0.01 5cdiu<i~ Chlcri~?e Edetate Disodium 0.01 NaOH/HCl q.s. pH 7.4 Purified Water_ q.s. 100 mL

2~ , The above formulation is prepared by first placing a portion of the purified water into a beaker and heating to 90°C. The hydroxypropylmethylcellulose (HPMC) is then added to the heated water and mixed by means of vigorous vortex stirring unti' all of the HPMC is dispersed.
s The resulting mixture is then allowed to cool while undergoing mixing in order to hydrate the HPMC. The resulting solution is then sterilized by means of autoclaving in a vessel having a liquid inlet and a hydrophobic, sterile air vent filter.
The sodium chloride and the edetate disodium are then added to a second io portion of the purified water and dissolved. The benzalkonium chloride is then added to the solution, and the pH of the solution is adjusted to 7.4 with O.1M NaOH/HC1. The solution is then sterilized by means of filtration.
21-Nor-5~-pregnan-3«,17«,20-triol is sterilized by either dry heat or ethylene oxide. If ethylene oxide sterilization is selected, aeration for at i5 least 72 hours at 50°C. is necessary. The sterilized steroid is weighed aseptically and placed into a pressurized ballmill container. The tyloxapol, in sterilized aqueous solution form, is then added to the ballmill container.
Sterilized glass balls are then added to the container and the contents of the container are milled aseptically at 225 rpm for 16 hours, or until all 2o particles are in the range of approximately 5 microns.
Under aseptic conditions, the micronized drug suspension formed by means of the preceding step is then poured into the HPMC solution with mixing. The ballmill container and balls contained therein are then rinsed with a portion of the solution containing the sodium chloride, the edetate disodium and 25 benzalkonium chloride. The rinse is then added aseptically to the HPMC
solution. The final volume of the solution is then adjusted with purified water and, if necessary, the pH of the solution is adjusted to pH 7.4 with NaOH/HCI.

The following formulation is representative of the antiinflartunatory compositions of the present invention.
Co~~nent s 4,9(11)Pregnadien-17«,21-diol-3,20- 1.0 dione-21-acetate Dexamethasone 0.1 Tyloxapol 0.01 to 0.05 HPMC 0.5 m Benzalkonium Chloride 0.01 Sodium Chloride 0.8 Edetate Disodium 0.01 NaOH/HC1 q.s. pH 7.4 Purified Water q.s. 100 mL

is The above formulation is prepared in the same manner set forth in Example 2, sterilizing and adding the dexamethasone to the steroid before placing both into a pressurized ballmill container.
The following formulation is another example of the antiinflammatory 2o compositions of the present invention.

W~

Tetrahydrocortisol 1.0 Prednisolone Acetate 1.0 Tyloxapol 0.01 to 0.05 is H PMC 0 . 5 Benzalkonium Chloride 0:01 Sodium Chloride 0.8 Edetate Disodium 0.01 NaOH/HCl q.s. pH 7.4 3o Purified Water q.s. 100 mls The above formulation is prepared in the same manner set forth in Example 2, sterilizing and adding the prednisolone acetate to the steroid before placing both into a pressurized ballmill container.
The following formulations are representative of compositions used for the treatment of angiogenesis dependent diseases.
FORMULATION FOR ORAL ADMINISTRATION
Tablet:
10-1000 mg of angiostatic steroid with inactive ingredients such io as starch, lactose and magnesium stearate can be formulated according to procedures known to those skilled in the art of tablet formulation.
FORMULATION FOR STERILE INTRAOCULAR INJECTION
each mL contains:

Angiostatic Steroid 10-100 mg Sodium Chloride 7.14 mg Potassium Chloride 0.38 mg Calcium chloride dihydrate 0.154 mg 2o Magnesium chloride hexahydrate 0.2 mg Dried sodium phosphate 0.42 mg Sodium bicarbonate 2.1 mg Dextrose 0.92 mg Hydrochloric acid or sodium hydroxide to adjust pH to approximately 7.2 Water for injection a 1 7 FORMULATION FOR TOPICAL OCULAR SOLUTION
21-Nor-5-pregnan-3,17-20-triol 1.09'0 -3-phosphate s Benzalkonium chloride 0.01%

HPMC 0 . 5fe Sodium chloride 0.8f Sodium phosphate 0.28%

Edetate disodium 0.01%

io NaOH/HCl q.s. pH 7.2 Purified Water q.s. 100 ml FORMULATION FOR TOPICAL OCULAR SUSPENSION
Ipgredient Amount i(wt.%) is 4,9(11)-Pregnadien-17«,21- 1.0 diol-3,20-dione-21-acetate Tyloxapol 0.01 to 0.05 HPMC 0.5 8enzalkonium chloride 0.01 2o Sodium chloride 0.8 Edetate Oisodium 0.01 NaOH/HCl q.s. pH 7.4 Purified Water q.s. 100 mL
The formulation is prepared by first placing a portion of the purified 2s water into a beaker and heating to 90°C. The hydroxypropylmethylcellulose (HPMC) is then added to the heated water and mixed by means of vigorous vortex stirring until all of the HPMC is dispersed. The resulting mixture is then allowed to cool while undergoing mixing in order to hydrate the HPMC. The resulting solution is then sterilized by means of autoclaving in a vessel 3o having a liquid inlet and a hydrophobic, sterile air vent filter.

The sodium chloride and the edetate disodium are then added to a second portion of the purified water and dissolved. The benzalkonium chloride is then added to the solution, and the pH of the solution is adjusted to 7.4 with O.1M NaOH/HCI. The solution is then sterilized by means of filtration.
s The 4,9(11)-Pregnadien-17a,21-diol-3,20-dione-21-acetate is sterilized by either dry heat or ethylene oxide. If ethylene oxide sterilization is selected, aeration for at least 72 hours at 50°C is necessary. The sterilized 4,9(11)-Pregnadien-17a,21-diol-3,20-dione-21-acetate is weighed aseptically and placed into a pressurized ballmill container. The tyloxapol, in io sterilized aqueous solution form, is then added to the ballmill container.
Sterilized glass balls are then added to the container and the contents of the container are milled aseptically at 225 rpm for 16 hours, or until all part;rlP~ a.re in the range of approximately 5 microns.
Under aseptic conditions, the micronized drug suspension formed by means is of the preceding step is then poured into the HPMC solution with mixing.
The ballmill container and balls contained therein are then rinsed with a portion of the solution containing the sodium chloride, the edetate disodium and benzalkonium chloride. The rinse is then added aseptically to the HPMC
solution. The final volume of the solution is then adjusted with purified 2o water and, if necessary, the pH of the solution is adjusted to pH 7.4 with NaOH/HC1. The formulation will be given topically, in a therapeutically effective amount. In this instance, the phrase "therapeutically effective amount" means an amount which is sufficient to substantially prevent or reverse any ocular neovascularization. The dosage regimen used will depend 2s on the nature of the neovascularization, as well as various other factors such as the patient's age, sex, weight, and medical history.
~ple 9 FORMULATION FOR ORAL ADMINISTRATION
Tablet:
30 5-100 mg 21-Nor-5p-pregnan-3«-17«-20-triol with inactive ingredients such as starch, lactose and magnesium stearate can be formulated according to procedures known to those skilled in the art of tablet formulation.

Example 10 Formulation for Sterile Intraocular Injection each mL
contains:
4,9(11)-Pregnadien-17x.,21-diol-3,20-dione 10-100 mg Sodium Chloride 7.14 mg Potassium Chloride 0.38 mg Calcium chloride dehydrate 0.154 mg Magnesium chloride hexahydrate 0.2 mg ,.. v. v, -, ~- , i~zieQ SCidiieTt ~m:~Spmc,~E= 0.42 ma Sodium bicarbonate 2.1 mg .
Dextrose 0.92 mg Hydrochloric acid or sodium hydroxide to adjust pH tc appro:ximately 7.2 Water for injection E;tample 11 Inhibition of angiogenesis in the rabbit corneal neovascularization model:
The corneal pocket system of BenEzra (Am. J.
Ophthalmol 86:455-461, 1978) was used to induce corneal neovascularization in the rabbit. A small Elvax* pellet containing 0.5~g of lipopolysaccharide (LPS) was inserted into the middle of the corneal stroma and positioned 2.5 mm from the limbus. An additional Elvax:* pellet with or without 50,ug of angiostatic steroid was placed next to the LPS implant. The *Trade-mark 27a eyes were examined daily and the area of neovascularization calculated. Results after 8 days of LPS implantation are shown in Figure 1. THF - tetrahydrocortisol; A = 4,9(11)-Pregnadien-17a,21-diol-3,20-dione-21-acetate; B = 4,9(11)-Pregnadien-S 17a,21-diol-3,20-dione. As c:an be seen, A & B totally inhibited corneal neovascularization, whereas THF partially inhibited the neovascular re.>ponse.

Preparation of 58-Pregnan-118. 17«. 21-triol-20-one Tetrahydrocortisol-F-21-t-butvldiphenvlsil~rl ether (PS0384~J~
A solution of 4.75 g (17.3 mmol) of t-butyldiphenylchlorosilane in 5 ml of dry s DMF was added dropwise to a stirred solution of 5.7 g (15.6 mmol) of tetrahydrocortisol-F (Steraloids No. P9050) and 2.3 g (19 mmol) of 4-dimethylaminopyridine (DMAP) in 30 mL of dry DMF, under N2, at -25 to -30°C
(maintained with COZ - MeCN). After a further 20 min at -30°C, the mixture was allowed to warm to 23°C overnight.
io The mixture was partitioned between ether and water, a,~,d the erganic solution was washed with brine, dried (MgS04), filtered and concentrated to give 10.7 g of a white foam.
This material was purified by flash column chromatography (400 g silica; 62.5 to 70f. ether/hexane). The 3-siloxy isomer eluted first, followed by mixed i5 fractions, followed by the title compound. The concentrated mixed fractions (4.0 g) were chromatographed on the same column with 35% ethyl acetate/hexane.
The total yi e1 d of the 3-s i 1 oxy i sourer was 0 . 42 g ( 5%) , and of the t i t1 a compound, 5.05 g (53.5%). Continued elution with 25% MeOH/EtOAc allowed recovery of unreacted tetrahydrocortisol-F.
2o pS03842 NMR (200 MHz 1H) (CDC13): 40.63 (s, 3H, Me-18); 1.11 (s, 9H, t-Bu); 1.12 (s, 3H, Me-19); 2.57 (t, J-13, 1H, H-8); 2.6 (s, 1H, OH-17); 3.63 (sept, J=2.5, 1H, H-3); 4.15 (br s, 1H, H-11); 4.37 and 4.75 (AB, J=20, 2H, H-21); 7.4 (m, 6H) and 7.7 (m, 4H) (Phz).
25 NMR (200 MHz 1H) (DMSO-ds): b0.64 (s, 3H, Me-18); 1.02 (s, 9H, t-Bu); 1.07 (s, 3H, Me-19); 2.50 (t, J=13, 1H, H-8); 3.37 (m, 1H, H-3); 3.94 (d, J=2, 1H, OH-11); 4.00 (br s, 1H, H-11); 4.42 (d, J=5, 1H, OH-3); 4.38 and 4.83 (AB, J=20, 2H, H-21); 5.11 (s, 1H, OH-17); 7.45 (m, 6H) and 7.6 (m, 4H) (Ph2).
NMR (50.3 - MHz 13C) (CDC13): ~ (C-18); 19.3 (C-16); 23.7 (C-15); 26.3 (C-7); ~ (C-19); ~ (Mg3C); 27.2 (C-6); 30.9 (C-2); 3~ (C-8); 34.1 (Me3~);
34.8 (C-10); 35.2 (C-1); 36.2 (C-4); 39.7 (C-13); ~ (C-5); ~ (C-9); 47.4 (C-12); ~2~.1, (C-14); ~j~,$ (C-11); 68.9 (C-21); ~ (C-3); 89.8 (C-14); 127.8, 129.8, 132.8, 132.9, 135.7, 135.8 (diastereotopic Ph2); 208.8 (C-20).
s Underlined resonances showed inversion in the APT experiment. Assignments:
E. Breitmaier, W. Voelter "Carbon-13 NMR Spectroscopy," 3d ed., VCH, 1987; pp.
345-348.
IR (KBr) 3460, 2930, 2860, 1720, 1428, 1136, 1113, 1070, 1039, 703 cm-1.
This compound did not show a sharp melting point but turned to a foam at 80-io 100°C. Numerous attempts at recrystallization failed.
~~,egnan-11 ~. ? 7~s 21-tri e1 -20-one A solution of PS03842 (0.91 g, 1.50 mnol) and thiocarbonyl diimidazole (1.05 g, 5.9 mmol) in 8 ml of anhydrous dioxane was refluxed under NZ for 3.5 h.
The cooled solution was partitioned between ether and water and the organic i5 solution was washed with brine, dried (MgS04), filtered and concentrated.
The residue was chromatographed (120 g SiOz, 35% EtOAc/hexane) giving 0.86 g (80%) of the imidazolyl thioester.
A solution of 0.75 g (1.05 mmol) of this compound in 100 mL of anhydrous dioxane was added dropwise over 2.2 h to a rapidly stirred, refluxing solution Zo of 1.6 mL (5.9 mmol) of Bu3SnH in 100 mL of anhydrous dioxane under N2.
After a further 1 h at reflux, the solution was cooled, concentrated and the residue chromatographed (200 g SiOz, 9% EtOAc/hexane) giving 0.43 g (70%) of the 3-deoxy-21-silyl ether. This material was dissolved in 20 mL of methanol;
Bu4NF~3HZ0 (0.50 g, 1.6 mnol) was added, and the mixture was heated to reflux is under NZ for 4 h. The cooled solution was diluted with 2 volumes of EtOAc, concentrated to 1/4 volume, partitioned (EtOAc/HZO), and the organic solution was washed with brine, dried (MgS04), filtered and concentrated. The residue (0.40 g) was chromatographed (30 g SiOz, 40fo EtOAc/hexane) to give 0.25 g (989'0) of an of 1 .
3o This oil was crystallized (n-BuCI) to afford 0.14 g of the title compound as a white solid, m.p. 167-170°C.

IR (KBr): 3413 (br), 2934, 1714, 1455, 1389, 1095, 1035 cm-1.
MS (CI): 351 (M +1).
NMR (200 MHz 1H, DMSO-d6): b0.69 (s, 3H, Me-18); 1.14 (s, 3H, Me-19); 0.8-2.0 (m); 2.5 (t, J=13, 1H, H-8); 3.96 (d, J=2, 1H, OH-11); 4.1 (br s, 1H, H-s 11); 4.1 and 4.5 (AB, further split by 5 Hz, 2H, H-21); 4.6 (t, J=5, 1H, OH-21); 5.14 (s, 1H, OH-17).
Calc'd for Cz1H34O4: C, 71.96; H, 9.78.
Found: C, 71.69; H, 9.66.
io P~oaratlon of 21-~lethvl -5B-yreqnan-3«, 11,x. 17«, 21-tetrol-20-one 21-methyl ether Sodium hydride (60% oil dispersion, 0.10 g, 2.5 mmol) was added to a stirred solution of tetrahydrocortisol-F (0.73 g, 2.0 mnol) and CH3I (0.60 mL, 9.6 mnol) in 8 mL of anhydrous DMF under N2. Hydrogen was evolved, and the is temperature rose to 35°C. After 1 h, the mi xture was di 1 uted wi th EtOAc, extracted with water (until neutral) and brine, dried (MgS04), filtered and concentrated. The residue was chromatographed (70 g Si02, 80% EtOAc/hexane) to give 0.17 g of a white solid, MS (CI) = 395 (M +1). This material was recrystallized (EtOAc-n-BuCI) to afford 0.12 g (169'0) of the title compound as 2o a feathery white solid, m.p. 208-213 °C.
IR (KBr): 3530, 3452, 2939, 2868, 1696 (s, CO), 1456, 1366, 1049 cm-1.
NMR (200 MHz 1 H, DMSO-d6): b0.74 (s, 3H, Me-18); 1.09 (s, 3H, Me-19); 1.14 (d, J=6.6, 3H, C-21 Me); 0.8-2.0 (m); 2.47 (t, J=13, 1H, H-8); 3.18 (s, 3H, OMe); 3.35 (m, 1H, H-3); 4.00 (d, J=2, 1H, OH-11); 4.07 (br s, 1H, H-11); 4.37 25 (q, J=6.6, 1H, H-21); 4.43 (d, J=5, 1H, OH-3); 5.16 (s, 1H, OH-17).
Calc'd for C23H38O5: C, 70.01; H, 9.71.
Found: C, 70.Ofi; H, 9.76.

31.
Preparation of 3~-Azido-5B-pre~gn~~~s 17«.21-trrjQL 20~.on~ 21-acetate A solution of triphenylphosphine (2.6 g, 10 mmol) in 10 mL of toluene was s carefully added to a stirred solution of PS03842 (see Example 4) (1.75 g, 2.90 mmol), diphenylphosphoryl azide (2.2 ml, 10.2 mmol) and diethyl azodicarboxylate (1.55 mL, 10 mmol) under Nz, keeping the internal temperature below 35°C (exothermic). The solution was stirred for 1.2 h, then diluted with ether, washed with water and brine, dried (MgSOQ), filtered and is concentrated and the residue (9.5 g, oil) chromatographed 175 g SiOz, I5%
EtOAc/hexane) giving 1.83 g of a viscous oil.
A solution of 1.73 g of this material and 1.75 g (5.5 mmol) of Bu4NF-3Hz0 in 20 mL of methanol was refluxed under Nz for 2.5 h. The crude product (1.94 g) was isolated with ethyl acetate and chromatographed (100 g SiOz, 50%
is EtOAc/hexane) giving 0.60 g (56%) of a white semisolid. Trituration (4:1 hexane-ether) gave 0.57 g (53%) of a solid.
A stirred solution of 0.40 g of this material in 3 mL of dry pyridine was treated with 0.3 ml of acetic anhydride and stirred overnight at 23°C
under Nz. The mixture was quenched with 1 mL of methanol, stirred for 15 min, zo di 1 uted wi th ether, washed wi th 1 d aqueous HCl , water (unti 1 neutral ) , bri ne, dried (MgS04), filtered and concentrated. The residue (0.41 g, oil) was chromatographed (35 g SiOz, 33% EtOAc/hexane) to afford 0.33 g (7fi%) of the title compound as a white foam, m.p. 80-90°C (dec).
IR (KBr): 3505, 2927, 2866, 2103 (vs), 1721 (sh 1730), 1268, 1235 cm 1.
25 NMR (200 MHz 1H, CDC13): b0.92 (s, 3H, Me-18); 1.21 (s, 3H, Me-19); 1.0-2.1 (m); 2.17 (s, 3H, Ac); 2.25 (s 1H, OH-17); 2.74 (m, 1H, H-8); 3.97 (br s, 1H, H-3); 4.31 (br s, 1H, H-11); 4.94 (AB, J=17, w =60, 2H, H-21).
Calc'd for Cz3H3sNsOsv C, 63.72; H, 8.14; N, 9.69.
Found: C, 63.39; H, 8.18; N, 9.45.

Example 15 Preparation of 3B-Acetamido-5B-pregnan-118.
17«-21-triol-2~-one-21-acetate A solution of 3~-azido-5~-pregnan-11~,17«,21-triol-20-one-21-acetate (0.15 g, s 0.35 mmol) in 8 mL of absolute ethanol containing 0.03 g of 10% Pd on C was stirred under H2 ( 1 atm) at 23°C for 2 h. The mixture was filtered and concentrated, the residue dissolved in EtOAc, the basic material extracted into 1 ~ aqueous HC1, liberated (NaZC03), extracted (EtOAc) and the organic extract washed with water (until neutral) and brine, dried (MgS04), filtered io and concentrated to provide 58 mg of a solid.
This material was acetylated (1.0 rnl of dry pyridine, 0.20 mL of Ac~O, 23°C, N2, overnight), followed by workup (as described far the steroid of Example 14 (last step]) affording a crude product that was chromatographed (25 g SiOz, EtOAc). This product was triturated with ether to afford 51 mg (33%) of is product as a white solid, m.p. 179-181°C.
MS (CI, isobutane): (M +1) = 450 (M~), 432, 391, 371, 348.
IR (KBr): 3398 (br), 2932, 2865, 1720 (sh. 1740), 1652, 1538, 1375, 1265, 1236 cm-1.
NMR (200 MHz 1H, CDC13): b0.89, 1.22, 1.99, 2.17 (all s, 3H); 1.0-2.2 (m);
20 2.7 (t, J-13, 1H, H-8); 3.03 (s, 1H, OH-17); 4.2 (br s, 1H, H-11); 4.3 (br s, 1H, H-3); 4.96 (AB, J=17.5, Av=42, 2H, H-21); 5.8 (d, J=10, 1H, NH).

Claims (14)

1. Use of a therapeutically effective amount of a composition comprising an ophthalmically acceptable excipient and a compound of the formula:

wherein R1 is H, .beta.-CH3 or .beta.-C2H5;
R2 is F, C9-C11 double bond, C9-C11 epoxy, H or C1;
R3 is H, OR26, OC(=O)R27, halogen, C9-C11 double bond, C9-C11 epoxy, =O, -OH, -O- alkyl (C1-C12), -OC(=O)alkyl(C1-C12), -OC(=O)N (R)2 or -OC(=O)OR7, and R is hydrogen, alkyl (C1-C4), or phenyl and each R is the same or different, and R7 is alkyl (C1-C12);
R4 is H, CH3, Cl or F;

R5 is H, OH, F, Cl, Br, CH3, phenyl, vinyl or allyl;
R6 is H or CH3;
R9 is CH2CH2OR26, CH2CH2OC(=O)R27, H, OH, CH3, F, =CH2, CH2C(=O)OR28, OR26, O(C=O)R27 or O(C=O)CH2(C=O)OR26;
R10 is -C.ident.CH, -CH=CH2, halogen, CN, N3, OR26, OC(=O)R27, H, OH, CH3 or R10 forms a second bond between positions C-16 and C-17;
R12 is H or forms a double bond with R1 or R14;
R13 is halogen, OR26, OC(=O)R27, NH2, NHR26, NHC
(=O)R27, N(R26)2, NC(=O)R27, N3, H, -OH, =O, -O-P(=O)(OH)2, or -O-C(=O)-(CH2)COOH where t is an integer from 2 to 6;
R14 is H or forms a double bond with R12;
R15 is H, =O or -OH;
R23 is -OH, O-C(=O)-R11, -OP(O)-(OH)2, -O-C(=O)-(CH2)t COOH or R23 with R10 forms a cyclic phosphate wherein t is an integer from 2 to 6; and R11 is -Y-(CH2)n-X-(CH2)m-SO3H, -Y'-(CH2)p-X'-(CH2)q-NR16R17 or -Z(CH2)r Q, wherein, Y is a bond or -O-; Y' is a bond, -O-, or -S-; each of X and X' is a bond, -CON(R18)-, -N(R18)CO-, -O-, -S-, -S(O)-, or -S(O2)-; R18 is hydrogen or alkyl (C1-C4);
each of R16 and R17 is a lower alkyl group of from 1 to 4 carbon atoms optionally substituted with one hydroxyl;
n is an integer of from 4 to 9; m is an integer of from 1 to 5; p is an integer of from 2 to 9; q is an integer of from 1 to 5;

Z is a bond or -O-; r is an integer of from 2 to 9; and Q is one of the following:
(1) -R19-CH2COOH, wherein R19 is -S-, -S(O)-;
-S(O)2-, -SO2N(R20)-, or N(R20) SO2-; and R20 is hydrogen or lower alkyl-(C1-C4); with the proviso that the total number of carbon atoms is R20 and (CH2)r is not greater than 10; or (2) -CO-COOH; or (3) CON(R21)CH(R22)COOH, wherein R21 is H and R22 is H, CH3, -CH2COOH, -CH2CH2COOH, -CH2OH, -CH2SH, -CH2CH2SCH3, or -CH2Ph-OH, wherein Ph-OH is p-hydroxyphenyl;
or R21 is CH3 and R22 is H;
or -N(R21)CH(R22)COOH is -NHCH2CONHCH2COOH; and pharmaceutically acceptable salts thereof;
with the proviso that if R23 is a phosphate, it must form a cyclic phosphate, with R10 when R13 is =O, except for the compound, wherein R1 is .beta.-CH3, R2 and R3 taken together form a double bond between positions 9 and 11, R4 and R6 are hydrogen, R12 and R14 taken together form a double bond between positions 4 and 5, R5 is .alpha.-F, R9 is .beta.-CH3, R10 is .alpha.-OH, R13 and R15 are =O and R23 is -OP(O)-(OH)2;
R24 is C or O, and there may be a double bond between positions 1 and 2 when R24 is C;
R25 is C(R15)CH2-R23, OH, OR26, OC(=O)R27, R26, COOH, C(=O)OR26, CHOHCH2OH, CHOHCH2OR26, CHOHCH2OC(=O)R27, CH2CH2OH, CH2N(R26)2, CH2OH, CH2OR26, CH2O(C=O)R27, CH2O(P=O)(OH)2, CH2O(P=O)(OR26)2, CH2SH, CH2S-R26, CH2SC(=O)R27, CH2NC(O)R27, C(O)CHR28OH, C(O) CHR28OR26, C(=O)CHR28OC(=O)R27 or R10 and R25 taken together may be =C(R28)2, that is, an optionally alkyl substituted methylene group;

wherein, R26 is C1-C6 (alkyl, branched alkyl, cycloalkyl, haloalkyl, aralkyl, aryl; R27, is R26 or OR26; R28 is H, C1-C6 (alkyl, branched alkyl, cycloalkyl);
excepted from the compounds of Structure [A] are the compounds, wherein R23 is OH, OC(=O)R11, OP(O) (OH)2, or OC(=O)(CH2)t COOH;
also excepted from the compounds of Structure [A]
are the compound 3,11.beta.,17.alpha.,21-tetrahydroxy-5-pregnane-20-one (the 3-.alpha., 5-.beta.; 3-.alpha., 5-.alpha.; 3-.beta., 5-.alpha.; and 3-.beta., 5-.beta. isomers of tetrahydrocortisol) , wherein R15 is =O, R10 is .alpha.-OH, R1 is .beta.-CH3, R3 is .beta.-OH, R2 is H, R4 is H, R13 is .alpha.- or .beta.-OH, R14 is H, R12 is .alpha.- or .beta.-H, R5 is H, R6 is H, R9 is H, R24 is C, and R23 is OH;
for preventing or treating neovascularization.
2. The use of claim 1, wherein the neovascularization is associated with or is a result of head trauma, spinal trauma, septic or traumatic shock, stroke, hemorrhagic shock, cancer, arthritis, arteriosclerosis, angiofibroma, arteriovenous malformations, corneal graft neovascularization, delayed wound healing, diabetic retinopathy, granulations, burns, hemangioma, hemophilic joints, hypertrophic scars, neovascular glaucoma, nonunion fractures, Osler-Weber Syndrome, psoriasis, pyogenic granuloma, retrolental fibroplasia, scleroderma, solid tumors, trachoma, vascular adhesions, pterigium, solid tumor growth, chronic glaucoma, retinal detachment, sickle cell retinopathy, senile masculr degneration, rubeosis iritis, uveitis, neoplasms, Fuch's heterochromic iridocyclitis, corneal neovascularization, combined vitrectomy and lensctomy, retinal ischemia, choroidal vascular insufficiency, choroidal thrombosis, carotid artery ischemia, or contusive ocular injury.
3. Use of a therapeutically effective amount of a composition comprising an ophthalmically acceptable excipient and a compound of the formula:

wherein R1 is H, .beta.-CH3 or .beta.-C2H5;
R2 is F, C9-C11 double bond, C9-C11 epoxy, H or C1;
R3 is H, OR26, OC(=O)R27, halogen, C9-C11 double bond, C9-C11 epoxy, =O, -OH, -O- alkyl (C1-C12), -OC(=O)alkyl(C1-C12), -OC(=O)N (R)2 or -OC(=O)OR7, and R is hydrogen, alkyl (C1-C4), or phenyl and each R is the same or different, and R7 is alkyl (C1-C12);

R4 is H, CH3, Cl or F;
R5 is H, OH, F, Cl, Br, CH3, phenyl, vinyl or allyl;
R6 is H or CH3;
R9 is CH2CH2OR26, CH2CH2OC(=O)R27, H, OH, CH3, F, =CH2, CH2C(=O)OR28, OR26, O(C=O)R27 or O(C=O)CH2(C=O)OR26;
R10 is -C.ident.CH, -CH=CH2, halogen, CN, N3, OR26, OC(=O)R27, H, OH, CH3 or R10 forms a second bond between positions C-16 and C-17;
R12 is H or forms a double bond with R1 or R14;
R13 is halogen, OR26, OC(=O)R27, NH2, NHR26, NHC
(=O)R27, N(R26)2, NC(=O)R27, N3, H, -OH, =O, -O-P(=O)(OH)2, or -O-C(=O)-(CH2)t COOH where t is an integer from 2 to 6;
R14 is H or forms a double bond with R12;
R15 is H, =O or -OH;
R23 is -OH, O-C(=O)-R11, -OP(O)-(OH)2, -O-C(=O)-(CH2)t COOH or R23 with R10 forms a cyclic phosphate wherein t is an integer from 2 to 6; and R11 is -Y-(CH2)n-X-(CH2)m-SO3H, -Y'-(CH2)p-X'-(CH2)q-NR16R17 or -Z(CH2)r Q, wherein, Y is a bond or -O-; Y' is a bond, -O-, or -S-; each of X and X' is a bond, -CON(R18)-, -N(R18)CO-, -O-, -S-, -S(O)-, or -S(O2)-;
R18 is hydrogen or alkyl (C1-C4); each of R16 and R17 is a lower alkyl group of from 1 to 4 carbon atoms optionally substituted with one hydroxyl;

n is an integer of from 4 to 9; m is an integer of from 1 to 5; p is an integer of from 2 to 9; q is an integer of from 1 to 5;
Z is a bond or -O-; r is an integer of from 2 to 9; and Q is one of the following:
(1) -R19-CH2COOH, wherein R19 is -S-, -S(O)-, -S(O)2-, -SO2N(R20)-, or N(R20)SO2-; and R20 is hydrogen or lower alkyl-(C1-C4); with the proviso that the total number of carbon atoms is R20 and (CH2)r is not greater than 10; or (2) -CO-COOH; or (3) CON(R21)CH(R22)COOH, wherein R21 is H and R22 is H, CH3, -CH2COOH, -CH2CH2COOH, -CH2OH, -CH2SH, -CH2CH2SCH3, or -CH2Ph-OH, wherein Ph-OH is p-hydroxyphenyl;
or R21 is CH3 and R22 is H;
or -N(R21)CH(R22)COOH is -NHCH2CONHCH2COOH; and pharmaceutically acceptable salts thereof;
with the proviso that if R23 is a phosphate, it must form a cyclic phosphate, with R10 when R13 is =O, except for the compound, wherein R1 is .beta.-CH3, R2 and R3 taken together form a double bond between positions 9 and 11, R4 and R6 are hydrogen, R12 and R14 taken together form a double bond between positions 4 and 5, R5 is .alpha.-F, R, is .beta.-CH3, R10 is .alpha.-OH, R13 and R15 are =O and R23 is -OP(O)-(OH)2, R24 is C or O, and there may be a double bond between positions 1 and 2 when R24 is C;
R25 is C(R15)CH2-R23, OH, OR26, OC(=O)R27, R26, COOH, C(=O)OR26, CHOHCH2OH, CHOHCH2OR26, CHOHCH2OC(=O)R27, CH2CH2OH, CH2CH2OR26, CH2CH2OC(=O)R27, CH2CN, CH2N3, CH2NH2, CH2NHR26, CH2N(R26)2, CH2OH, CH2OR26, CH2O(C=O)R27, CH2O(P=O)(OH)2, CH2O(P=O)(OR26)2, CH2SH, CH2S-R26, CH2SC (=O)R27, CH2NC(O)R27, C(O)CHR28OH, C(O) CHR28OR26, C(=O)CHR28OC(=O)R27 or R10 and R25 taken together is =C(R28)2, that is, an optionally alkyl substituted methylene group;
wherein, R26 is C1-C6 (alkyl, branched alkyl, cycloalkyl, haloalkyl, aralkyl, aryl; R27 is R26 or OR26;
R28 is H, C1-C6 (alkyl, branched alkyl, cycloalkyl);
excepted from the compounds of Structure A are the compounds, wherein R23 is OH, OC(=O)R11, OP(O)(OH)2, or OC(=O)(CH2)t COOH;
also excepted from the compounds of Structure A
are the compound 3,11.beta.,17.alpha.,21-tetrahydroxy-5-pregnane-20-one (the 3-.alpha., 5-.beta.; 3-.alpha., 5-.alpha.; 3-.beta., 5-.alpha.; and 3-.beta., 5-.beta. isomers of tetrahydrocortisol), wherein R15 is =O, R10 is .alpha.-OH, R1 is .beta.-CH3, R3 is .beta.-OH, R2 is H, R4 is H, R13 is .alpha.- or .beta.-OH, R14 is H, R12 is .alpha.- or .beta.-H, R5 is H, R6 is H, R9 is H, R24 is C, and R23 is OH;
for preventing or treating ocular neovascularization.
4. The use of claim 3, wherein the compound is used at a concentration of about 0.01, to 10.0 weight percent of the composition.
5. The use of claim 3, wherein the compound is used at a concentration of about 0.1 to 5.0 weight percent of the composition.
6. The use of any one of claims 3 to 5, wherein the ocular neovascularization is in the front of an eye.
7. The use of claim 6, wherein the ocular neovascularization is in a cornea.
8. The use of any one of claims 3 to 5, wherein the ocular neovascularization is in the back of an eye.
9. A commercial package comprising a therapeutically effective amount of a composition comprising an ophthalmically acceptable excipient and a compound as defined in claim 1 or 3, together with instruction for its use in preventing or treating neovascularization.
10. Use of a therapeutically effective amount of a composition comprising an ophthalmically acceptable excipient and a compound selected from the group consisting of: 21-nor-5.beta.-pregnan-3.alpha.,17.alpha.,20-triol-3-acetate; 21-nor-5.alpha.-pregnan-3.alpha.,17.alpha.,20-triol-3-phosphate; 21-nor-5.beta.-pregn-17(20)en-3.alpha., 16-diol; 21nor-5.beta.-pregnan-3.alpha., 17.beta.,20-triol;
20-acetamide-21-nor-5.beta.-pregnan-3.alpha.,17.alpha.-diol-3-acetate;
3.beta.-acetamido-5.beta.-pregnan-11.beta.,17.alpha.,21-triol-20-one-21-acetate;
21-nor-5.alpha.-pregnan-3.alpha.,17.beta.,20-triol; 21.alpha.-methyl-5.beta.-pregnan-3.alpha.,11.beta.,17.alpha.,21-tetrol-20-one-21-methyl ether; 20-azido-21-nor-5.beta.-pregnan-3.alpha.,17.alpha.-diol; 20(carbethoxymethyl)thio-21-nor-5.beta.-pregnan-3.alpha.,17.alpha.-diol; 20-(4-fluorophenyl)thio-21-nor-5.beta.-pregnan-3.alpha.,17.alpha.-diol; 16.alpha.-(2-hydroxyethyl)-17.beta.-methyl-5.beta.-androstan-3.alpha.,17.alpha.-diol; 20-cyano-21-nor-5.beta.-pregnan-3.alpha.,17.alpha.-diol; 17.alpha.-methyl-5.beta.-androstan-3.alpha.,17.beta.-diol; 21-nor-5.beta.-pregn-17(20)en-3.alpha.-ol; 21-or-5.beta.-pregn-17(20) en-3.alpha.-ol-3-acetate;
21-nor-5-pregn-17(20)-en-3.alpha.-ol-16-acetic acid 3-acetate;
3.beta.-azido-5.beta.-pregnan-11.beta.,17.alpha.,21-triol-20-one-21-acetate;
and 5.beta.-pregnan-11.beta.,17.alpha.,21-triol-20-one; 4-androsten-3-one-17.beta.-carboxylic acid; 17.alpha.-ethynyl-5(10)-estren-17.beta.-ol-3-one; and 17.alpha.-ethynyl-1,3,5(10)-estratrien-3,17.beta.-diol, for preventing or treating ocular neovascularization.
11. The use of claim 10, wherein the ocular neovascularization is in the front of an eye.
12. The use of claim 11, wherein the ocular neovascularization is in the back of an eye.
13. The use of any one of claims 10 to 12, wherein the compound is used at a concentration of about 0.01 to 10.0 weight percent of the composition.
14. The use of any one of claims 10 to 12, wherein the compound is used at a concentration of about 0.1 to 5.0 weight percent of the composition.
CA002425841A 1988-10-31 1992-11-23 Angiostatic steroids Expired - Lifetime CA2425841C (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
US79616991A true 1991-11-22 1991-11-22
US07/796,169 1991-11-22
US89244892A true 1992-06-02 1992-06-02
US07/892,448 1992-06-02
US07/941,485 US5371078A (en) 1988-10-31 1992-09-08 Angiostatic steroids and methods and compositions for controlling ocular hypertension
US07/941,485 1992-09-08
CA 2123405 CA2123405C (en) 1991-11-22 1992-11-23 Angiostatic steroids

Publications (2)

Publication Number Publication Date
CA2425841A1 CA2425841A1 (en) 1993-05-27
CA2425841C true CA2425841C (en) 2006-01-10

Family

ID=27419924

Family Applications (4)

Application Number Title Priority Date Filing Date
CA002425841A Expired - Lifetime CA2425841C (en) 1988-10-31 1992-11-23 Angiostatic steroids
CA 2123405 Expired - Lifetime CA2123405C (en) 1988-10-31 1992-11-23 Angiostatic steroids
CA002425849A Expired - Lifetime CA2425849C (en) 1988-10-31 1992-11-23 Angiostatic steroids
CA002425846A Abandoned CA2425846A1 (en) 1988-10-31 1992-11-23 Angiostatic steroids

Family Applications After (3)

Application Number Title Priority Date Filing Date
CA 2123405 Expired - Lifetime CA2123405C (en) 1988-10-31 1992-11-23 Angiostatic steroids
CA002425849A Expired - Lifetime CA2425849C (en) 1988-10-31 1992-11-23 Angiostatic steroids
CA002425846A Abandoned CA2425846A1 (en) 1988-10-31 1992-11-23 Angiostatic steroids

Country Status (10)

Country Link
EP (4) EP1236470A3 (en)
JP (1) JP3378245B2 (en)
AT (1) AT232540T (en)
AU (1) AU678961B2 (en)
CA (4) CA2425841C (en)
DE (2) DE69232925T2 (en)
DK (1) DK0614463T3 (en)
ES (1) ES2187503T3 (en)
HK (1) HK1012638A1 (en)
WO (1) WO1993010141A2 (en)

Families Citing this family (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5990099A (en) * 1988-10-31 1999-11-23 Alcon Laboratories, Inc. Angiostatic agents and methods and compositions for controlling ocular hypertension
US5969168A (en) * 1991-01-07 1999-10-19 Pherin Corporation Androstanes for inducing hypothalamic effects
DE4311987A1 (en) * 1993-04-07 1994-10-13 Schering Ag new glucocorticoids
BR9307867A (en) * 1993-06-15 1996-07-30 Pherin Corp Androstane steroids as neurochemical primer change in human hypothalamic function and duty pharmaceutical compositions and related methods
US5504074A (en) * 1993-08-06 1996-04-02 Children's Medical Center Corporation Estrogenic compounds as anti-angiogenic agents
US5646136A (en) * 1994-01-04 1997-07-08 Duke University Methods of inhibiting angiogenesis and tumor growth, and treating ophthalmologic conditions with angiostatic and therapeutic steroids
WO1997041867A1 (en) * 1996-05-09 1997-11-13 Alcon Laboratories, Inc. Use of steroid compounds to prevent non-cancerous tissue growth
DE69731302D1 (en) 1996-07-22 2004-11-25 Renovo Ltd Use of substances that promote estrogen effect, for treatment of wounds
AU1935501A (en) * 1999-12-09 2001-06-18 Alcon Universal Limited Id protein inhibitors for treating ocular diseases
US6726918B1 (en) 2000-07-05 2004-04-27 Oculex Pharmaceuticals, Inc. Methods for treating inflammation-mediated conditions of the eye
JP2004522711A (en) * 2000-11-16 2004-07-29 アルコン マニュファクチャリング,リミティド Combination therapy for lowering and controlling intraocular pressure
JP2004514702A (en) 2000-11-29 2004-05-20 オキュレックス ファーマシューティカルズ, インコーポレイテッド Intraocular implant for preventing transplant rejection in the eye
ES2311592T3 (en) * 2001-03-28 2009-02-16 Santen Pharmaceutical Co., Ltd. Remedies for diseases of retina and choroid containing steroids as active ingredient.
US20030119800A1 (en) * 2001-06-18 2003-06-26 Manolagas Stavros C. Bone anabolic compounds and methods of use
US20040214806A1 (en) 2002-09-03 2004-10-28 Iok-Hou Pang Use of non-feminizing estrogens as retinoprotective agents for the treatment of glaucoma
TWI320712B (en) * 2001-09-05 2010-02-21 Alcon Inc The use of non-feminizing estrogens as retinoprotective agents for the treatment of glaucoma
US20050048099A1 (en) 2003-01-09 2005-03-03 Allergan, Inc. Ocular implant made by a double extrusion process
US8081598B2 (en) 2003-02-18 2011-12-20 Qualcomm Incorporated Outer-loop power control for wireless communication systems
US8023950B2 (en) 2003-02-18 2011-09-20 Qualcomm Incorporated Systems and methods for using selectable frame durations in a wireless communication system
US20040160922A1 (en) 2003-02-18 2004-08-19 Sanjiv Nanda Method and apparatus for controlling data rate of a reverse link in a communication system
US7660282B2 (en) 2003-02-18 2010-02-09 Qualcomm Incorporated Congestion control in a wireless data network
US7155236B2 (en) 2003-02-18 2006-12-26 Qualcomm Incorporated Scheduled and autonomous transmission and acknowledgement
US8391249B2 (en) 2003-02-18 2013-03-05 Qualcomm Incorporated Code division multiplexing commands on a code division multiplexed channel
GB0304927D0 (en) 2003-03-04 2003-04-09 Resolution Chemicals Ltd Process for the production of tibolone
US7215930B2 (en) 2003-03-06 2007-05-08 Qualcomm, Incorporated Method and apparatus for providing uplink signal-to-noise ratio (SNR) estimation in a wireless communication
US8705588B2 (en) 2003-03-06 2014-04-22 Qualcomm Incorporated Systems and methods for using code space in spread-spectrum communications
AT488240T (en) * 2003-04-18 2010-12-15 Advanced Medicine Res Inst Means for behanldung of diseases for application to the eye
WO2004093882A1 (en) * 2003-04-18 2004-11-04 Advanced Medicine Research Institute Remedies for diseases to be applied to eye
US8477592B2 (en) 2003-05-14 2013-07-02 Qualcomm Incorporated Interference and noise estimation in an OFDM system
US7315527B2 (en) 2003-08-05 2008-01-01 Qualcomm Incorporated Extended acknowledgement and rate control channel
US8489949B2 (en) 2003-08-05 2013-07-16 Qualcomm Incorporated Combining grant, acknowledgement, and rate control commands
US20050239760A1 (en) * 2004-04-23 2005-10-27 Alcon, Inc. Angiostatic agents and methods and compositions for controlling ocular hypertension
US20050244469A1 (en) 2004-04-30 2005-11-03 Allergan, Inc. Extended therapeutic effect ocular implant treatments
EP1789056A1 (en) * 2004-06-29 2007-05-30 Jado Technologies GmbH Use of steroid-derived pharmaceutical compositions for treating disorders relating to pathological processes in lipid rafts
EP2446888A3 (en) * 2005-07-12 2012-08-15 DMI Biosciences, Inc. Use of danazol for the treatment of uveitis
MX2010012976A (en) 2008-05-28 2011-05-31 Validus Genetics Non-hormonal steroid modulators of nf-kb for treatment of disease.
SG176939A1 (en) 2009-06-22 2012-01-30 Dmi Acquisition Corp Method for treatment of diseases
US9198921B2 (en) 2010-04-05 2015-12-01 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-κB for treatment of disease
CN104968350A (en) 2012-12-19 2015-10-07 安皮奥制药股份有限公司 Method for treatment of diseases
EP3250291A4 (en) 2015-01-30 2018-07-18 Biomed Valley Discoveries, Inc. Crystalline c21h22c12n4o2 malonate
CA2975048A1 (en) 2015-01-30 2016-08-04 Biomed Valley Discoveries, Inc. Crystalline forms of c21h22ci2n4o2

Family Cites Families (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB790452A (en) * 1955-04-01 1958-02-12 Upjohn Co Steroids and the preparation thereof
US3658856A (en) * 1969-09-02 1972-04-25 Syntex Corp Process for preparing useful 17alpha-hydroxy-20-keto-21-acyloxy pregnanes
US4041055A (en) * 1975-11-17 1977-08-09 The Upjohn Company Process for the preparation of 17α-hydroxyprogesterones and corticoids from androstenes
US4342702A (en) * 1981-05-18 1982-08-03 The Upjohn Company Metallated halogenated acetylene corticoid synthesis
US4357279A (en) * 1981-05-18 1982-11-02 The Upjohn Company Preparation of corticoids from 17-keto steroids
US4617299A (en) * 1983-12-19 1986-10-14 Knepper Paul A Method for the prevention of ocular hypertension, treatment of glaucoma and treatment of ocular hypertension
US4812448A (en) * 1984-10-22 1989-03-14 Knepper Paul A Method for the prevention of ocular hypertension, treatment of glaucoma and treatment of ocular hypertension
US4600538A (en) * 1984-08-02 1986-07-15 The Upjohn Company Corticosteroids from 17-keto steroids via 20-cyano-Δ17 (20)-pregnanes
JPH0224250B2 (en) * 1984-10-31 1990-05-29 Kureha Chemical Ind Co Ltd
US4975537A (en) * 1985-10-23 1990-12-04 The Upjohn Company Δ9(11) -angiostatic steroids
AT66002T (en) * 1985-10-23 1991-08-15 Upjohn Co Angiostatic steroids.
US4686214A (en) * 1985-10-30 1987-08-11 Alcon Laboratories, Inc. Anti-inflammatory compounds for ophthalmic use
US5036048A (en) * 1986-03-07 1991-07-30 Schering Corporation Angiotensin II receptor blockers as antiglaucoma agents
US4863912A (en) * 1986-05-19 1989-09-05 New York Medical College Use of tetrahydrocortisol in glaucoma therapy
EP0374185B1 (en) * 1987-08-14 1993-02-10 The Upjohn Company IMPROVED 9$g(a)-DEHALOGENATION PROCESS
AT162719T (en) * 1989-08-28 1998-02-15 Alcon Lab Inc ophthalmic preparation
US4876250A (en) * 1988-10-31 1989-10-24 Alcon Laboratories, Inc. Methods for controlling ocular hypertension with angiostatic steroids
JPH04506066A (en) * 1989-06-16 1992-10-22
JP2985007B2 (en) * 1990-02-09 1999-11-29 武田薬品工業株式会社 Angiogenesis inhibitors
CA2081205C (en) * 1990-06-11 2001-02-27 John W. Wilks Steroids which inhibit angiogenesis

Also Published As

Publication number Publication date
DK614463T3 (en)
JP3378245B2 (en) 2003-02-17
JPH07501081A (en) 1995-02-02
AU678961B2 (en) 1997-06-19
DK0614463T3 (en) 2003-03-31
CA2425849C (en) 2007-02-27
WO1993010141A2 (en) 1993-05-27
CA2425841A1 (en) 1993-05-27
EP0614463A1 (en) 1994-09-14
AT232540T (en) 2003-02-15
WO1993010141A3 (en) 1993-09-02
EP1236470A3 (en) 2004-09-01
ES2187503T3 (en) 2003-06-16
EP1236471A3 (en) 2004-12-15
HK1012638A1 (en) 2003-05-09
DE69232925T2 (en) 2003-06-18
CA2425846A1 (en) 1993-05-27
CA2425849A1 (en) 1993-05-27
DE69232925D1 (en) 2003-03-20
EP1236471A2 (en) 2002-09-04
CA2123405A1 (en) 1993-05-27
EP1236469A3 (en) 2004-09-01
AU3223593A (en) 1993-06-15
EP1236469A2 (en) 2002-09-04
EP1236470A2 (en) 2002-09-04
CA2123405C (en) 2008-01-15
EP0614463B1 (en) 2003-02-12

Similar Documents

Publication Publication Date Title
US6646001B2 (en) Use of non-steroidal anti-inflammatory agents in combination with prostaglandin FP receptor agonists to treat glaucoma and ocular hypertension
US9011915B2 (en) Conveniently implantable sustained release drug compositions
Soong et al. Adverse reactions to virgin silk sutures in cataract surgery
AU604236B2 (en) Intraocular dosage compositions and method of use
US5021404A (en) Angiostatic collagen modulators
EP0713393B1 (en) Estrogenic compounds as anti-angiogenesis agents
US20060141049A1 (en) Triamcinolone compositions for intravitreal administration to treat ocular conditions
US6051576A (en) Means to achieve sustained release of synergistic drugs by conjugation
JP5682991B2 (en) Convenient implantable sustained-release drug formulation
CA2011956C (en) Sodium hyaluronate composition
US6342524B1 (en) Use of non-steroidal anti-inflammatory agents in combination with compounds that have FP prostaglandin agonist activity to treat glaucoma and ocular hypertension
US6162801A (en) External ophthalmic preparation containing vitamin D
JP4065373B2 (en) Pharmaceutical formulations comprising as an active ingredient thalidomide
US5420120A (en) Anti-inflammatory glucocorticoid compounds for topical ophthalmic use
AU2007225305B2 (en) Ophthalmic compositions comprising povidone-iodine
US5442053A (en) Salts and mixtures of hyaluronic acid with pharmaceutically active substances, pharmaceutical compositions containing the same and methods for administration of such compositions
CA1340825C (en) Hyaluronic acid fraction for use as a drug delivery system for medicaments
US20040147494A1 (en) Use
US20110117189A1 (en) Ophthalmic compositions for treating pathologies of the posterior segment of the eye
EP0749437B1 (en) Pharmaceutical uses of steroid derivatives
US3780177A (en) 17-butyrate,21-ester derivatives of 6alpha,9alpha-difluoroprednisolone,compositions and use
US20040014734A1 (en) Farnesoid X-activated receptor agonists
Atkinson et al. Action of some steroids on the central nervous system of the mouse. II. Pharmacology
EP0637203B1 (en) Regulation of the immune system
US20050020555A1 (en) Estrogenic compounds as anti-mitotic agents

Legal Events

Date Code Title Description
EEER Examination request
MKLA Lapsed
MKEC Expiry (correction)

Effective date: 20121210

MKEC Expiry (correction)

Effective date: 20121210